Formulations for transdermal or transmucosal application

ABSTRACT

The present invention relates generally to formulations for transdermal or transmucosal administration of an active agent. The invention is a substantially malodorous-free and irritation free transdermal formulation which is substantially free of long chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 10/343,570 filed May 19, 2003, which is the USnational stage of International Application PCT/EP01/09007 filed Aug. 3,2000, and claims priority to U.S. Provisional Patent Applications60/510,613 filed Oct. 10, 2003 and 60/453,604 filed Mar. 11, 2003. Eachprior application is expressly incorporated herein in its entirety byreference thereto.

BACKGROUND OF THE INVENTION

[0002] 1. Field of Invention

[0003] The present invention relates generally to formulations for thetransdermal or transmucosal delivery of active agents. In particular,the present invention is directed to a substantially malodorous-free andirritation-free transdermal formulation which is substantially free oflong chain fatty alcohols, long chain fatty acids, and long-chain fattyesters, and which delivers effective therapeutic levels of an activeagent.

[0004] 2. Background Art

[0005] Transdermal and/or transmucosal delivery of active agents providea convenient, pain-free, and non-invasive method of administering activeagents to a subject. Additionally, the administration of active agents,such as drugs, through the skin or mucosal surface avoids thewell-documented problems associated with the “first pass effect”encountered by oral administration of active agents. As known in theart, orally administered drugs are absorbed and enter the bloodstreamwhere they are transported by the portal vein directly to the liverbefore entering the general circulation of the body. If the drug issubject to a high hepatic clearance, i.e., it is rapidly metabolized bythe liver, then a substantial fraction of the absorbed dose is extractedfrom the blood and metabolized before it ever reaches the systemiccirculation. The consequence of this “first pass effect” phenomenon is asignificant reduction in the bioavailability of the drug. In someinstances, the first pass effect is so large as to render oraladministration of a drug ineffective.

[0006] Although the transdermal and/or transmucosal delivery of activeagents overcome some of the problems associated with oral administrationof active agents, such as that described above, they are not free oftheir own drawbacks. Problematically, transdermal drug delivery systemsare typically restricted to low-molecular weight drugs and those withstructures having the proper lipophilic/hydrophilic balance. Highmolecular weight drugs, or drugs with too high or low hydrophilicbalance, often cannot be incorporated into current transdermal systemsin concentrations high enough to overcome their impermeability throughthe stratum comeum. Specifically, polar drugs tend to penetrate the skintoo slowly, and since most drugs are of a polar nature, this limitationis significant.

[0007] Efforts have been made in the art to chemically modify thebarrier properties of skin to permit the penetration of certain agents(since diffusion is primarily controlled through the stratum comeum),enhance the effectiveness of the agent being delivered, enhance deliverytimes, reduce the dosages delivered, reduce the side effects fromvarious delivery methods, reduce patient reactions, and so forth.

[0008] In this regard, penetration enhancers have been used to increasethe permeability of the dermal surface to drugs, and are often protonsaccepting solvents such as dimethyl sulfoxide (DMSO) anddimethylacetamide. Other penetration enhancers that have been studiedand reported as effective include 2-pyrrolidine, N,N-diethyl-m-toluamide(Deet), 1-dodecal-azacycloheptane-2-one N,N-dimethylformamide,N-methyl-2-pyrrolidine, calcium thioglycolate, hexanol, fatty acids andesters, pyrrolidone derivatives, derivatives of 1,3-dioxanes and1,3-dioxolanes, 1-N-dodecyl-2-pyrrolidone-5-carboxylic acid,2-pentyl-2-oxo-pyrrolidineacetic acid,2-dodecyl-2-oxo-1-pyrrolidineacetic acid,1-azacycloheptan-2-one-2-dodecylacetic acid, and aminoalcoholderivatives, including derivatives of 1,3-dioxanes, among others.

[0009] The most common penetration enhancers, however, are toxic,irritating, oily, odiferous, or allergenic. Specifically, thepenetration enhancers used and thought to be necessary to transdermallydeliver active agents such as steroid hormones, namely, compounds suchas long chain fatty acids such as oleic acids, fatty alcohols such aslauryl alcohol and long-chain fatty esters such as isopropyl myristate,tend to include aliphatic groups that make the formulations oily andmalodorous.

[0010] For example, U.S. Pat. No. 5,891,462 teaches the use of laurylalcohol as a permeation enhancer for estradiol and norethindroneacetate. Such formulations are not appealing to the user nor to anyoneelse in close proximity to the user. Although this particular patentdiscloses three examples of estradiol or norethindrone acetateformulations having no lauryl alcohol component, such formulations arecomparative examples that are intended to illustrate the long heldposition that long chain fatty alcohols such as lauryl alcohol arenecessary to transdermally deliver norethindrone acetate in combinationwith estradiol to a subject.

[0011] Additionally, for example, the known testosterone gelformulations FORTIGEL® and TOSTRELLE® (Cellegy Pharma, South SanFrancisco, Calif.), both include ethanol, propanol, propylene glycol,carbomer, triethanolamine, purified water, and oleic acid as apermeation enhancer, the latter being responsible for the irritating andmalodorous characteristics of these formulations. Also, TESTIM®(Auxilium Pharmaceuticals, Norristown, Pa.) is a 1% testosterone gel andincludes pentadecalactone, acrylates, glycerin, polyethylene glycol(PEG), and pentadecalactone as a permeation enhancer. It is a veryodoriferous compound. Also, TESTIM® is not desirable because it containsundesirable amounts of glycerin which are not well tolerated by theskin.

[0012] Thus, there is a need for a transdermal formulation thatadequately delivers active agents to patients with skin tolerability,but does not include the unpleasant odor common to the prior artformulations.

SUMMARY OF THE INVENTION

[0013] The present invention relates to transdermal or transmucosalmalodorous-free and irritation-free formulations comprising an activeagent and delivery vehicle. In particular, the formulation comprises atleast one active agent; and a delivery vehicle, which may comprise a C₂to C₄ alkanol, a polyalcohol, and a permeation enhancer of monoalkylether of diethylene glycol present in an amount sufficient to providepermeation enhancement of the active agent through mammalian dermal ormucosal surfaces. The formulation is substantially free of long-chainfatty alcohols, long chain fatty acids and long-chain fatty esters inorder to avoid potential undesirable odor and irritation effects causedby such compounds during use of the formulation. Thus, advantageously,the formulations of the present invention do not include theundesirable-odor causing and irritation causing permeation enhancersthat were once thought to be necessary for such transdermal ortransmucosal formulations.

[0014] In accordance with the invention, the polyalcohol may beadvantageously present in an amount between about 1% and 30% by weightof the vehicle. The monoalkyl ether of diethylene glycol may be presentin an amount of about 0.2% and 25% by weight of the vehicle and thealkanol may be present in an amount between about 5 to 75% by weight ofthe vehicle. Generally, the alkanol can be present in a hydroalcoholicmixture with water.

[0015] The alkanol may be an ethanol, isopropanol, or n-propanol.Preferably, the alkanol is ethanol. The polyalcohol may be propyleneglycol, butylene glycol, hexylene glycol, and ethylene glycol.Preferably, the polyalcohol is propylene glycol. The permeation enhancerof monoalkyl ether of diethylene is, for example, diethylene glycolmonoethyl ether or diethylene glycol monomethyl ether. Preferably, thepermeation enhancer is diethylene glycol monoethyl ether.

[0016] The active agent may be selected from androgens, estrogens, orprogestogens or any combination thereof, for example, androgens plusestrogens, androgens plus progestogens, or androgens plus estrogens,plus progestogens, provided that when the active agent is an estrogen ora progestogen, a therapeutically effective amount of a progestogen orestrogen, respectively, is not present in the formulation. Particularlypreferred active agents include: androgens, anti-androgens, estrogens,anti-estrogens, progestogens, anti-progestogens, adrenergic agonists,analgesics, sedatives, amides, arylpiperazines, nerve agents,antineoplastics, anti-inflammatory agents, anticholinergics,anticonvulsants, antidepressants, antiepileptics, antihistaminics,antihypertensives, muscle relaxants, diuretics, bronchodilators, andglucocorticoids. If desired, the active agent may be present incombination with a secondary active agent for concurrent administrationsubject to the previously stated provision.

[0017] The formulation can further include at least one of a gellingagent, neutralizing agent; buffering agent, moisturizing agent,humectant, surfactant, antioxidant, emollient, or buffer, and the like.The formulation may be applied in the form of a gel, lotion, cream,spray, aerosol, ointment, emulsion, suspension, liposomal system,lacquer, patch, bandage, or occlusive dressing and the like.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The features and benefits of the invention will now become moreclear from a review of the following detailed description ofillustrative embodiments and the accompanying drawings, wherein:

[0019]FIG. 1 is a graph depicting drug flux over time for testosteronein formulations including various amounts of lauryl alcohol (LA) in anin vitro model using human excised skin and 10 mg testosterone/cm² inthe loading chamber (n=3-4±SD).

[0020]FIG. 2 is a graph depicting drug flux over time for testosteronein formulations including various amounts of lauryl alcohol (LA) in anin vitro model using human excised skin and 50 mg testosterone/cm² inthe loading chamber (n=3-4±SD).

[0021]FIGS. 3A, B & C are graphs depicting median total, free andbioavailable testosterone serum concentrations following administrationof 1%T+0%LA gel in vivo over a sampling period on days 1, 7, 14, and 21,respectively.

[0022]FIGS. 3D, E & F are graphs depicting mean bioavailable and freetestosterone serum concentrations after different dose regimens andtreatments with a 1%T +2%LA gel in vivo over a sampling period on days1, 7, 14, respectively.

[0023]FIG. 4A is a graph depicting mean serum concentrations ofestradiol (E2) following single dose administration of E2+0%LA gel(a=0.75 mg E2; b=1.50 mg E2).

[0024]FIG. 4B is a graph depicting mean trough concentrations of E2 overtime following repeated administration of E2+0%LA gel (a=0.75 mg E2;b=1.50 mg E2).

[0025]FIG. 4C is a graph depicting mean trough concentrations of E2 overtime following repeated administration of E2+0%LA gel in one subject(2.5 g; ±SD; 240.0 H-value out of scale (28.0 ng/dl)).

[0026]FIG. 4D is a graph depicting individual trough concentrations ofE2 over time following repeated administration of E2+0%LA gel at bothdoses.

[0027]FIG. 4E is a graph depicting mean serum concentrations of E2following multiple dose administration of E2+0%LA gel (a=0.75 mg E2;b=1.50 mg E2).

[0028]FIG. 4F is a graph depicting mean serum concentrations of estrone(E1) following single dose administration of E2+0%LA gel (a=0.75 mg E2;b=1.50 mg E2).

[0029]FIG. 4G is a graph depicting mean trough concentrations of E1following repeated administration of E2+0%LA gel (a=0.75 mg E2; b=1.50mg E2).

[0030]FIG. 4H is a graph depicting mean serum concentrations of E1following multiple dose administration of E2+0%LA gel (a=0.75 mg E2;b=1.50 mg E2).

[0031]FIG. 4I is a graph depicting mean serum concentrations ofestrone-sulfate (E1 -sulfate) following single dose administration ofE2+0%LA gel (a=0.75 mg E2; b=1.50 mg E2).

[0032]FIG. 4J is a graph depicting mean trough concentrations ofE1-sulfate following multiple dose administration of E2+0%LA gel (a=0.75mg E2; b=1.50 mg E2).

[0033]FIG. 4K is a graph depicting mean serum concentrations ofE1-sulfate following multiple dose administration of E2+0%LA gel (a=0.75mg E2; b=1.50 mg E2).

[0034]FIG. 5A is a graph depicting mean change from baseline in dailymoderate-to-severe hot flush rate after E2+0%LA gel at various doses(Intent-to-treat efficacy population (“ITT”); Method of last observationcarried forward for subjects who discontinued early (“LOCF”).

[0035]FIG. 5B is a graph depicting mean change from baseline in dailymoderate-to-severe hot flush rate after E2+0%LA gel at various doses(Evaluable-LOCF).

[0036]FIG. 5C is a graph depicting mean change from baseline in dailyhot flush mean severity after E2+0%LA gel at various doses (ITT-LOCF).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] The formulations of the present invention may be clear, waterwashable, cool to the touch, quick drying, spreadable and/or anon-greasy formulations, such as a gel. In other aspects of theinvention, the formulation may be a spray, ointment, aerosol, patch,buccal and sublingual tablets, suppositories, vaginal dosage form, orother passive or active transdermal devices for absorption through theskin or mucosal surface. The formulations of the present invention maybe applied directly to the skin such as by, for example and notlimitation, a gel, ointment, or cream or indirectly though a patch,bandage, or other occlusive dressing.

[0038] Advantageously, the substantial omission of the long chain fattyalcohols, long-chain fatty acids, and long-chain fatty esters provides aformulation that does not have the unpleasant odor, irritation, and/orgreasy texture caused by formulations of the prior art that include oneor more of such compounds. Thus, the formulation in accordance with thepresent invention will result in greater patient compliance. Theinventive formulations are substantially free of such alcohols, fattyacids, and long-chain fatty esters so that the odors associated withthose compounds do not emanate from the formulation. In this regard,“substantially free” means an amount which does not impart a perceptibleodor to the formulation at a distance of 1 meter. Such formulations arealso deemed to be substantially odor free. For the purpose of exampleand illustration, a formulation comprising fatty alcohols, fatty acidsand/or fatty esters in an amount of less than about 0.04% by weight ofthe formulation is substantially odor free.

[0039] The present invention relates generally to formulations forproviding active agents to subjects. The invention further relates toformulations for the transdermal or transmucosal administration ofactive agents that are substantially free of malodorous, and irritationcausing long-chain fatty alcohols, long-chain fatty acids, andlong-chain fatty esters. Surprisingly, the formulation of the presentinvention can achieve sufficient absorption to result in an effectivedosage of the selected active agent(s) circulating in serum without theinclusion of the long-chain fatty alcohols, the long-chain fatty acidsand the long-chain fatty esters that have been used to date.

[0040] The delivery vehicle of the present invention preferablycomprises a C₂ to C₄ alkanol, a polyalcohol, and a permeation enhancerof monoalkyl ether of diethylene glycol in an amount sufficient toprovide permeation enhancement of the active agent through mammaliandermal or mucosal surfaces.

[0041] In accordance with the invention, the polyalcohol isadvantageously present in an amount between about 1% and 30% of thevehicle, preferably from 3% to 20% w/w and more preferably from about 4% to 10% w/w. The monoalkyl ether of diethylene glycol is present in anamount of about 0.2% and 25%, preferably between about 1% to 15% w/w andmore preferably between about 2% to 8% w/w. The alkanol is present in anamount between about 5 to 75% w/w, preferably between about 15% to 65%,and more preferably between about 20% and 55% w/w. The alkanol can bepresent in a hydroalcoholic mixture with water. The mixture is presentin an amount between about 40% and 98% of the delivery vehicle, with thealcohol being present in an amount between about 5% to 80% w/w of thehydroalcoholic mixture, and the water present in an amount between about20% to 95% w/w of the hydroalcoholic mixture. Preferably, the alcohol ispresent in an amount of about 50 to 60% and the water in an amount of 50to 40% of the hydroalcoholic mixture.

[0042] For example, the monoalkyl ether of diethylene glycol isdiethylene glycol monomethyl ether or diethylene glycol monoethyl etheror mixtures thereof. Also for example, the polyalcohol is propyleneglycol, dipropylene glycol or mixtures thereof. The polyalcohol and thepermeation enhancer may be in present in a weight ratio of about 2:1 to1:1. Alternatively, the polyalcohol and permeation enhancer may bepresent in a weight ratio of about 1.25:1 to 1.2 to 1.

[0043] For the purpose of illustration and not limitation, the alkanolmay be a C2 to C4 alcohol such as ethanol, isopropanol, or n-propanol.The alkanol is preferably ethanol. As known in the art, the amount ofthe alcoholic component of the formulation may be selected to maximizethe diffusion of the active agent through the skin while minimizing anynegative impact on the active agent itself or desirable properties ofthe formulation.

[0044] The formulations of the invention may include at least one or acombination of active agents. The “active agent” is used herein to referto a substance or formulation or combination of substances orformulations of matter which, when administered to an organism (human oranimal) induces a desired pharmacologic and/or physiologic effect bylocal and/or systemic action.

[0045] The active agent of the formulation may be selected from thegroup including: androgens, anti-androgens, estrogens, anti-estrogens,progestogens, anti-progestogens, adrenergic agonists, analgesics,sedatives, amides, arylpiperazines, nerve agents, antineoplastics,anti-inflammatory agents, anticholinergics, anticonvulsants,antidepressants, antiepileptics, antihistaminics, antihypertensives,muscle relaxants, diuretics, bronchodilators, and glucocorticoids.Alternatively, depending on the course of treatment for the mammaliansubject, any other suitable active agent may be used. The following listof active agents is purely an illustration and should not be construedas a limitation.

[0046] Hormones. In one embodiment of the invention the active agentincludes any one of or a combination of steroid or nonsteroid hormones,their precursors, derivatives and analogs, esters and salts thereofincluding, but not limited to: dehydroepiandosterone (DHEA) and itsderivatives, e.g., salts, optical isomers, racemic, androgens, estrogensand progestins (also referred to as progestogens). For example, thecombination of hormones may be androgens plus estrogens, androgens plusprogestogens, or androgens plus estrogens plus progestogens.

[0047] Examples of androgens which may be used in this invention includetestosterone (17-β-hydroxyandrostenone), and testosterone esters, suchas testosterone enanthate, testosterone propionate, testosteronedecanoate and testosterone cypionate. The aforementioned testosteroneesters are commercially available or may be readily prepared usingtechniques known to those skilled in the art or described in thepertinent literature. Also, pharmaceutically acceptable esters oftestosterone and 4-dihydrotestosterone, typically esters formed from thehydroxyl group present at the C-17 position (such as enanthate,propionate, cypionate, phenylacetate, acetate, isobutyrate, buciclate,heptanoate, decanoate, undecanoate, caprate and isocaprate esters); andpharmaceutically acceptable derivatives of testosterone such as methyltestosterone, testolactone, oxymetholone and fluoxymesterone may beused.

[0048] Other suitable androgenic agents that may be used in theformulations of the present invention include, but are not limited to:the endogenous androgens, precursors and derivatives thereof, includingandrosterone, androsterone acetate, androsterone propionate,androsterone benzoate, androstenediol, androstenediol-3-acetate,androstenediol-17-acetate, androstenediol-3,17-diacetate,androstenediol- 17-benzoate, androstenediol-3-acetate-17-benzoate,androstenedione, sodium dehydroepiandrosterone sulfate,4-dihydrotestosterone (DHT), 5 adihydrotestosterone, dromostanolone,dromostanolone propionate, ethylestrenol, nandrolone phenpropionate,nandrolone decanoate, nandrolone furylpropionate, nandrolonecyclohexanepropionate, nandrolone benzoate, nandrolonecyclohexanecarboxylate, oxandrolone, stanozolol, as well as androgenreceptor agonists, and antiandrogens.

[0049] Examples of estrogens and progestogens which may be useful inthis invention include estrogens such as 17 beta-estradiol, estradiol,estradiol benzoate, estradiol 17 beta-cypionate, estriol, estrone,ethynil estradiol, mestranol, moxestrol, mytatrienediol, polyestradiolphosphate, quinestradiol, quinestrol; progestogens such asallylestrenol, anagestone, chlormadinone acetate, delmadinone acetate,demegestone, desogestrel, dimethisterone, dydrogesterone,ethynilestrenol, ethisterone, ethynodiol, ethynodiol diacetate,flurogestone acetate, gestodene, gestonorone caproate, haloprogesterone,17-hydroxy-16-methylene-progesterone, 17 alpha-hydroxyprogesterone, 17alpha-hydroxygesterone caproate, lynestrenol, medrogestone,medroxyprogesterone, megestrol acetate, melengestrol, norethindrone,norethindrone acetate, norethynodrel, norgesterone, norgestimate,norgestrel, norgestrienone, 19-norprogesterone, norvinisterone,pentagestrone, progesterone, natural progesterone, promegestone,quingestrone, trengestone.

[0050] Other Active Agents. Other suitable active agents include but arenot limited to anti estrogens, such as tamoxifen, 4-OH tamoxifen; antiprogestogens and anti androgens, alpha-adrenergic agonists, such asbudralazine, clonidine, epinephrine, fenoxazoline, naphazoline,phenylephrine, phenylpropanolamine, beta-adrenergic agonists such asformoterol, methoxyphenamine, alpha-adrenergic blockers such asdoxazosin, prazosin, terazosin, trimazosin, yohimbine, beta-adrenergicblockers such as atenolol, bisoprolol, carteolol, carvedilol,metoprolol, nadolol, penbutolol, analgesics (Narcotics or Non-Narcotics)such as buprenorphine, dihydromorphine, metazocine, methadone, morphine,morphine derivatives, nicomorphine, oxymorphone.

[0051] Sedatives. Amides. Arylpiperazines. Other suitable active agentsinclude sedatives and anxyolitics for instance benzodiazepinederivatives such as alprazolam, bromazepam, flutazolam, ketazolam,lorazepam, prazepam; amides such as butoctamide, diethylbromoacetamide,ibrotamide, isovaleryl diethylamide, niaprazine, tricetamide,trimetozine, zolpidem, zopiclone; arylpiperazines such as buspirone

[0052] Nerve Agents. Antineoplastics. Anti-inflammatory agents. Othersuitable active agents include nerve agents for smoking cessation, suchas nicotine, nicotine citrate and nicotine tartrate; antineoplasticagents such as 5-fluorouracil; anti-inflammatory agents; anesthetics;antianginals; anticholinergics; anticonvulsants; antidepressants;antiepileptics; antiestrogen; antihistaminics; antiparkinsonians;bronchodilators; diuretics; glucocorticoids; muscle relaxants; narcoticantagonists; antihypothyroids such as levothyroxine, thyroid, thyroxine;antihypertensives for instance benzothiadiazine derivatives such ascaptopril, cilazapril, enalapril, lisinopril, perindopril, ramipril;guanidine derivatives such as guanethidine; quinazoline derivatives suchas alfuzosin; reserpine derivatives such as reserpine, sulfonamidederivatives such as furosemide; others such as minoxidil, amlodipine,doxazosin mesylate, felodipine, moxonidine, nicardipine hydrochloride,nifedipine, prazosin hydrochloride, etc and calcium channel blockerssuch as arylalkylamines such as bepridil, ditiazem, fendiline,gallopamil, terodiline, verapamil; dihydropyridine derivatives such asfelodipine, isradipine, nicardipine, nifedipine, nilvadipine,nimodipine, nisoldipine, nitrendipine, piperazine; derivatives such asflunarisine; others such as perhexiline; calcium regulator such ascalcifediol, calcitonin, calcitriol, clodronic acid, dihydrotachysterol,elcatonin, etidronic acid, ipriflavone, pamidronic acid, parathyroidhormone, teriparatide acetate.

[0053] The formulation may further include a thickening agent or gellingagent present in an amount sufficient to alter the viscosity of theformulation. A gelling agent can be selected from the group including:carbomer, carboxyethylene or polyacrylic acid such as Carbopol 980 or940 NF, 981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020, 2050,934P NF, 971P NF, 974P NF, Noveon AA-1 USP; cellulose derivatives suchas ethylcellulose, hydroxypropylmethylcellulose (HPMC),ethylhydroxyethylcellulose (EHEC), carboxymethylcellulose (CMC),hydroxypropylcellulose (HPC) (Klucel different grades),hydroxyethylcellulose (HEC) (Natrosol grades), HPMCP 55, Methocelgrades; natural gums such as arabic, xanthan, guar gums, alginates;polyvinylpyrrolidone derivatives such as Kollidon grades;polyoxyethylene polyoxypropylene copolymers such as Lutrol F grades 68,127. Other gelling agents include chitosan, polyvinyl alcohols, pectins,veegum grades. A tertiary amine, such as triethanolamine or trolamine,can be included to thicken and neutralize the system.

[0054] A polymer or copolymer of acrylic acid, such as a carbomer actsas a gelling forming and facilitates the release of lipophilic activeagent and penetration enhancer. Preferably, the gelling agent is LutrolF grades and Carbopol grades. The gelling agent is present from about0.2 to about 30.0% w/w of the formulation depending on the type ofpolymer. For example, the gelling agent is preferably present in anamount between about 0.5% to 2% for polyacrylic acids, and between about1 to 5% for celluloses.

[0055] The amount and the type of the gelling agent in the formulationmay be selected to provide the desired product consistency and/orviscosity to facilitate application to the skin.

[0056] Preservatives. The formulation may further include preservativessuch as, but not limited to, benzalkonium chloride and derivatives,benzoic acid, benzyl alcohol and derivatives, bronopol, parabens,centrimide, chlorhexidine, cresol and derivatives, imidurea, phenol,phenoxyethanol, phenylethyl alcohol, phenylmercuric salts, thimerosal,sorbic acid and derivatives. The preservative is present from about 0.01to about 10.0% w/w depending on the type of compound.

[0057] Antioxidant. The formulation may optionally include antioxidantssuch as but not limited to tocopherol and derivatives, ascorbic acid andderivatives, butylated hydroxyanisole, butylated hydroxytoluene, fumaricacid, malic acid, propyl gallate, metabisulfates and derivatives. Theantioxidant is present from about 0.001 to about 5.0% w/w of theformulation depending on the type of compound

[0058] Buffers. The formulation may further include buffers such ascarbonate buffers, citrate buffers, phosphate buffers, acetate buffers,hydrochloric acid, lactic acid, tartric acid, diethylamine,triethylamine, diisopropylamine, aminomethylamine. Although otherbuffers as known in the art may be included. The buffer may replace upto 100% of the water amount within the formulation.

[0059] Humectant. The formulation may further include humectant, such asbut not limited to glycerin, propylene, glycol, sorbitol, triacetin. Thehumectant is present from about 1 to 10.0% w/w of the formulationdepending on the type of compound.

[0060] Sequestering agent. The formulation may further include asequestering agent such as edetic acid. The sequestering agent ispresent from about 0.001 to about 5.0% w/w of the formulation dependingon the type of compound.

[0061] Surfactant. The formulation may further include anionic,non-ionic or cationic surfactants. The surfactant is present from about0.1% to about 30.0% w/w of the formulation depending on the type ofcompound.

[0062] pH regulator. Optionally, the formulation may include a pHregulator, generally, a neutralizing agent, which can optionally havecrosslinking function. By way of example and not limitation, the pHregulator may include a ternary amine such as triethanolamine,tromethamine, tetrahydroxypropylethylendiamine, NaOH solution. The pHregulator is present in the formulations in about 0.05 to about 2.0%w/w.

[0063] Moisturizers and Emollients. Optionally, the formulation mayinclude moisturizers and/or emollients to soften and smooth the skin orto hold and retain moisture. By way of example and not limitation,moisturizers and emollients may include cholesterol, lecithin, lightmineral oil, petrolatum, and urea.

[0064] For any particular formulation, the active agent and otheringredients may be selected to achieve the desired drug delivery profileand the amount of penetration desired. The optimum pH may also bedetermined and may depend on, for example, the nature of the hormone,the base, and degree of flux required.

[0065] In certain preferred embodiments of the present invention, theformulation may have the following formula. TABLE 1 Estradiol 0.01%-2%  Carbomer 0.05%-4%   Triethanolamine (adjust to pH 5.9) 0.05%-1%  Alcohol 20%-65% Propylene glycol  1%-15% Diethylene glycol monoethylether  1%-15% Ion Exchange Purified Water q. ad. 20%-65%

[0066] TABLE 2 Testosterone 0.01%-10%   Carbomer 0.05%-4%  Triethanolamine (adjust to pH 5.9) 0.05%-1%   Alcohol 20%-65% Propyleneglycol  1%-15% Diethylene glycol monoethyl ether  1%-15% Ion ExchangePurified Water q. ad. 20%-65%

[0067] TABLE 3 Estradiol 0.01%-1% Carbomer 940  1.2% Triethanolamine(adjust to pH 5.9)  0.4% Alcohol 46.28% Propylene glycol    6%Diethylene glycol monoethyl ether    5% Disodium EDTA  0.06% IonExchange Purified Water q. ad.   100%

[0068] TABLE 4 Testosterone 0.01%-10% Carbomer 980  1.2% Triethanolamine(adjust to pH 5.9)  0.4% Alcohol 46.28% Propylene glycol    6%Diethylene glycol monoethyl ether    5% Disodium EDTA  0.06% IonExchange Purified Water q. ad.   100%

[0069] TABLE 5 Testosterone   1% Carbomer 980  1.2% Triethanolamine(adjust to pH 5.9)  0.4% Ethanol 47.5% Propylene glycol   6% Diethyleneglycol monoethyl ether   5% Disodium EDTA 0.06% Ion Exchange PurifiedWater q. ad.  100%

[0070] The formulation of the present invention is advantageous at leastfor the following reasons. First, the formulations of the presentinvention are substantially free of long-chain fatty alcohols,long-chain fatty acids, and long-chain fatty esters. Surprisingly, theformulations exhibit skin penetration sufficient to deliver an effectivedosage of the desired active agent(s) to the user. This is an unexpectedadvantage that those of ordinary skill in the art would not have readilydiscovered since it had been generally understood that long-chain fattyalcohols, long-chain fatty acids, and long chain fatty esters would berequired to enhance skin penetration to permit an effective dose of anactive agent to penetrate the skin.

[0071] Second, because the formulation does not include aliphatic acidgroups, such as fatty acids, that are commonly included in topical gels,it does not have the odor or oily texture which is associated with thatingredient as in presently-available gels. Third, the absence oflong-chain fatty alcohols, long-chain fatty acids, and long-chain fattyesters means that the irritation potential is lower and that there isless chance for the components to interact, reducing the need forantioxidants or preservatives in the formulation. Numerous studiesacknowledge the irritation causing potential of unsaturated fatty acidssuch as oleic acid. See, Tanojo H. Boelsma E, Junginger HE, Ponec M,Bodde HE, “In vivo human skin barrier modulation by topical applicationof fatty acids,” Skin Pharmacol Appl. Skin Physiol. 1998 Mar-Apr; 11 (2)87-97. It is to be understood, however, that if such preservatives aredesired, the invention encompasses formulations which includeantioxidants or preservatives. The reduction in the number ofingredients is advantageous at least in reducing manufacturing costs,possible skin irritation. Additionally, the reduced number ofingredients increases the storage stability of the formulation bydecreasing the chance that the ingredients will interact prior to beingdelivered. This does not, however, imply that additional ingredientscannot be included in the formulation for particular aesthetic and/orfunctional effects. For example, the formulation may optionally includeone or more moisturizers for hydrating the skin or emollients forsoftening and smoothing the skin. Glycerin is an example of such asuitable moisturizing additive.

[0072] The formulation may be applied once daily, or multiple times perday depending upon the condition of the patient. The formulation of theinvention may be applied topically to any body part, such as the thigh,abdomen, shoulder, and upper arm. In one embodiment, a formulation inthe form of a gel is applied to about a 5 inch by 5 inch area of skin.Application may be to alternate areas of the body as applicationsalternate. For example, the gel may be applied to the thigh for thefirst application, the upper arm for the second application, and back tothe thigh for the third application. This may be advantageous inalleviating any sensitivity of the skin to repeated exposure tocomponents of the formulation.

[0073] The invention includes the use of the formulations describedabove to treat subjects to increase circulating levels of active agentswithin the patient.

[0074] Preferred dosage units are capable of delivering an effectiveamount of the selected active agent over a period of about 24 hours. Byan “effective” or “therapeutically effective” amount of an active agentis meant a nontoxic, but sufficient amount of the agent to provide thedesired effect.

[0075] However, it will be appreciated by those skilled in the art thatthe desired dose will depend on the specific active agent as well as onother factors; the minimum effective dose of each active agent is ofcourse preferred to minimize the side effects associated treatment withthe selected active agent(s). The formulation is preferably applied on aregularly timed basis so that administration of the active agents issubstantially continuous.

EXAMPLES

[0076] The following examples are illustrative and should not beinterpreted as limiting.

Example 1

[0077] One embodiment of the formulation according to the invention is atopical gel having Testosterone 1.25% w/w, propylene glycol 5.95% w/w,Ethyl alcohol 45.46% w/w, Distilled water 45.67% w/w, Carbomer (Carbopol980 NF) 1.21% w/w, Triethanolamine 0.39% w/w, Disodium EDTA 0.06% w/w.

Example 2

[0078] One embodiment of the formulation according to the invention is agel composed by testosterone 1.00% w/w, diethylene glycol monoethylether 5.00% w/w, propylene glycol 6.00% w/w, ethanol 47.52% w/w,purified water 38.87% w/w, carbomer (CARBOPOL™ 980 NF) 1.20% w/w,triethanolamine 0.35% w/w, disodium EDTA 0.06% w/w.

Example 3

[0079] One embodiment of a formulation according to the invention is atopical hydroalcoholic gel formulation with 1% testosterone as theactive ingredient. The formulation has been studied in one Phase I/IImultiple dose, dose escalating clinical study in women. The study wasconducted to determine the effectiveness of the formulation for thetreatment of hypoactive sexual desire disorder (“HSDD”), in subjectsincluding surgically menopausal women with low testosterone levels.

[0080] This study showed that the testosterone gel dosing between about0.22 g to about 0.88 g formulation (2.2 to 8.8 mg/day testosterone)daily for 7 days resulted in average total and free testosterone serumconcentrations within the normal range or somewhat above the normalrange for pre-menopausal women.

Example 4

[0081] In vitro studies were conducted to determine the permeabilityprofile of testosterone in human surgically excised skin using thetestosterone formulation of Table 5 above (containing no lauryl alcohol,“1%T+0%LA”), as compared with other testosterone formulations containing1% and 2% lauryl alcohol (“1%T+1% or 2% LA”). The results of thesestudies are presented below in Tables 6, 7 and 8.

[0082] In the first study pieces of excised human skin were mounted inFranz Vertical usion Cells (Hansen Research Inc.). Approximately 10 mgof testosterone/cm² (1%T +0, 1 or 2%LA), were loaded in the loadingchamber over the skin, which was maintained at 35° C. Sampling of thereceptor solution was performed at selected intervals after loading. Thetestosterone flux and cumulative amount in the permeability study areshown below in Table 6. TABLE 6 Cum. Flux (μg/h · cm²) (μg/cm²) Amt.(SD) Time (h) 0% LA 1% LA 2% LA 0% LA 1% LA 2% LA 3 0.043 0.159 0.1010.129 0.478 0.303 6 0.093 0.468 0.307 0.410 1.884 1.225 9 0.062 0.3290.172 0.595 2.871 1.740 12 0.051 0.165 0.121 0.748 3.368 2.104 18 0.0270.049 0.047 0.911 3.664 2.388 24 0.026 0.036 0.052 1.070 3.883 2.699

[0083] The testosterone flux and cumulative amount for the gelcomprising approximately 1.25% testosterone, 5.00% Transcutol, 5.95%propylene glycol, 43.09% ethyl alcohol, 43.07% distilled water, 1.20%Carbopol 980NF, 0.38% triethanolamine, 0.059% EDTA are represented belowin Tables 7 and 8. TABLE 7 Testosterone In vitro flux (μg/h * cm²)* Mean+/− S.D. Example 1 described above 1.12 +/− 0.36

[0084] TABLE 8 Testosterone Cumulative Amount (μg/cm²) Mean +/− S.D.Time (h) Example 1 described above 0 0 6 10.25 +/− 4.97 12 20.40 +/−6.75 18 27.84 +/− 8.70 24  33.80 +/− 10.45

[0085]FIG. 1 is a graph depicting drug flux over time for testosteronein formulations including various amounts of lauryl alcohol (LA) in anin vitro model using human excised skin and 10 mg tosterone/cm² in theloading chamber (n=3-4±SD). The profile of 1%T+0%LA is different thanthe formulations containing lauryl alcohol. The profile is about 4 timeslower at 6 hours than the 2%LA formulation, but overall more consistent.All profiles showed a decrease in testosterone flux after 6 hours ofpermeation, possibly due to drug depletion.

[0086] Another permeation study was conducted using the method describedabove, except that approximately 50 mg of testosterone/cm² were loadedin the loading chamber over the skin. Sampling of the receptor solutionwas performed at selected intervals hours after loading. Thetestosterone flux and cumulative amount in the permeability study areshown below. TABLE 9 Flux μg/(h·cm²) Cum. μg/cm² Amt. (SD) Time (h) 0%LA 1% LA 2% LA 0% LA 1% LA 2% LA 3.0 0.448 0.872 0.900 1.345 2.617 2.7006.0 0.521 1.216 1.336 2.908 5.732 6.709 9.0 0.504 0.914 0.801 4.4218.473 9.112

[0087]FIG. 2 is a graph depicting drug flux over time for testosteronein formulations including various amounts of lauryl alcohol (LA) in anin vitro model using human excised skin and 50 mg testosterone/cm² inthe loading chamber (n=3-4±SD).

[0088] This study shows that the 1%T+0%LA has a lower permeation rate.However, the permeation profile was less variable making it potentiallymore desirable for use in women since testosterone levels must betitrated within a narrow range. Thus, these in vitro studies would leadone of ordinary skill in the art to believe that the inclusion of laurylalcohol in the formulation is required in the formulation in order toachieve suitable circulating levels of hormones. However, Applicantshave unexpectedly found that the inclusion of lauryl alcohol is notrequired in topical formulations to achieve an effective dose ofcirculating active agent penetration. This is especially true for FemaleSexual Dysfunction where required testosterone plasmatic levels arelower than testosterone therapeutic plasmatic levels observed to treathypogonadism.

Example 5

[0089] Experience with gel formulations and transdermal patchesgenerally show low rates of mild dermal toxicity with the gels andextensive skin reactions with the patches, probably related to theadhesive used or the occlusive nature of the patch. For instance, with atopical gel formulation of testosterone, a few patients had skinreactions, none of which required treatment or discontinuation of drug.In contrast, transient mild to moderate erythema was observed in themajority of patients treated with a transdermal patch, and some patientshad more severe reactions including blistering, necrosis, andulceration. See for example, Gelas B. Thébault J, Roux I, Herbrecht F.Zartarian M., “Comparative study of the acceptability of a new estradiolTx 11323 (A) gel and a transdermal matrix system,” Contraception,fertilité, sexualité, 1997 Jun; 25 (6):470-474).

Example 6

[0090] The objective of this study was to evaluate the safety andpharmacokinetic profiles of multiple doses of a 1%T+0%LA hydroalcoholicgel, in postmenopausal women. During the first 7 days of the study, thesubjects received daily topical applications of 0.22 g of a formulationincluding 1%T +0%LA (2.2 mg/day testosterone). On Days 8-14, thesubjects received 0.44 g of a formulation including 1%T +0%LA (4.4mg/day testosterone), and on Days 15-21, the subjects received 0.88 g ofa formulation including 1%T +0%LA (8.8 mg/day testosterone). There wasno washout period, prior to each dose escalation. The pharmacokineticresults for total, free and bioavailable testosterone are shown below.TABLE 10 Parameter Day 1 Day 7 Day 14 Total Testosterone Day 31 DailyDose 2.2 mg 2.2 mg 4.4 mg 8.8 mg N 7 7 7 7 C_(o) (ng/dL) 21.00 (6.0)42.43 (14.8) 68.71 (35.6) 87.00 (41.6) C_(avg)(ng/dL) 38.49 (17.0) 56.03(24.5) 91.99 (51.2) 141.49 (72.0) C_(max)(ng/dL) 69.86 (33.0) 113.57(92.9) 165.57 (113.8) 203.86 (128.3) C_(min)(ng/Dl) 19.00 (6.2) 31.14(15.6) 43.14 (20.6) 77.57 (27.9) T_(max) * (hr) 20 (20-24) 16 (1-24) 16(1-24) 20 (3-24) T_(min) * (hr) 1 (0-6) 6 (0-20) 6 (0-12) 0 (0-12) AUC923.79 (408.3) 1344.71 (588.5) 2207.79 (1228.1) 3395.64 (1728.8) (ng ·hr/dL) AR (ratio) — 1.59 (0.7) 2.32 (0.5) 3.59 (0.6) Day 21 FreeTestosterone Daily Dose 2.2 mg 2.2 mg 4.4 mg 8.8 mg N 7 7 7 7 C_(o)(pg/mL) 2.64 (1.0) 5.24 (1.8) 7.87 (3.2) 10.80 (7.4) C_(avg)(pg/mL) 4.81(1.8) 6.96 (1.9) 11.13 (5.4) 16.69 (7.3) C_(max) 8.84 (3.6) 15.79 (14.3)21.31 (19.5) 25.80 (16.0) (pg/mL) C_(min)(pg/mL) 2.26 (0.9) 3.67 (1.3)5.53 (2.2) 9.23 (4.9) T_(max) * (hr) 20 (20-24) 20 (3-24) 16 (1-24) 20(3-24) T_(min) * (hr) 1 (0-12) 9 (0-20) 9 (0-12) 0 (0-6) AUC (pg hr/mL)— 1.57 (0.6) 2.28 (0.5) 3.43 (0.8) Bioavailable Testosterone Daily Dose2.2 mg 2.2 mg 4.4 mg 8.8 mg N 7 7 7 7 C_(o) (ng/dL) 4.01 (2.1) 7.94(3.7) 12.56 (5.8) 16.27 (12.1) C_(avg) (ng/dL) 7.48 (3.4) 10.81 (3.6)16.47 (8.1) 25.04 (11.5) C_(max) (ng/dL) 13.33 (6.7) 25.57 (28.5) 32.14(29.4) 39.13 (27.1) C_(min) (ng/dL) 3.69 (1.7) 5.84 (2.7) 8.43 (3.6)13.84 (7.7) T_(max) * (hr) 20 (20-24) 16 (1-24) 16 (9-24) 20 (3-24) AUC(ng hr/dL) 179.4 (81.4) 259.52 (87.1) 395.23 (195.0) 600.94 (276.2) AR(ratio) — 1.59 (0.7) 2.26 (0.7) 3.48 (1.2)

[0091] FIGS. 3A-C are graphs depicting median total, free andbioavailable testosterone serum concentrations following administrationof 1%T+0%LA in vivo over a sampling period on days 1, 7, 14, and 21,respectively.

[0092] The average baseline total testosterone and free testosteroneconcentrations were 21.0 ng/dL and 2.6 pg/mL, respectively. After oneweek of 0.22 g daily doses of 1%T +0%LA, the average total testosteroneand free testosterone concentrations were 56.0 ng/dL and 7.0 pg/mL,respectively. One week of daily 0.44 g doses of 1%T+0%LA increased theaverage total testosterone and free testosterone concentrations to 92.0ng/dL and 11.1 pg/mL, respectively. Daily doses of 0.88 g 1%T+0%LA for 7days increased the average testosterone and free testosteroneconcentrations to 141.5 ng/dL and 16.7 pg/mL in the 7 subjects.

[0093] FIGS. 3D-F are graphs depicting mean bioavailable and freetestosterone serum concentrations after different dose regimens andtreatments with 1%T+2%LA in vivo over a sampling period on days 1, 7,14, respectively. When like testosterone dosages are compared, this datashows that in vivo testosterone levels are not substantially changed bythe inclusion of lauryl alcohol. Therefore, contrary to the in vitrofindings, lauryl alcohol was not necessary to achieve effective serumlevels in vivo.

[0094] This study demonstrated that 1%T 0% LA has the potential toelevate free testosterone concentrations in women with low endogenoustestosterone production. The 0.22 g dose, corresponding to 2.2 mgtestosterone, resulted in average free testosterone concentrationstowards the upper limit of normal. For the 0.44 g dose, average freetestosterone concentrations were 1.6 times the upper limit of normalwhile average free testosterone concentrations for the 0.88 g dose wereapproximately 2.4 times the upper limit of normal.

[0095] Further, the 1%T+0%LA formulation has been administered in dailytestosterone doses of 2.2, 4.4, and 8.8 mg (doses of 0.22 g/day, 0.44g/day, and 0.88 g/day, each applied for 7 days, respectively) in onePhase I/II study. The formulation was well tolerated in this study. Noserious or significant adverse events were reported. No significantchanges in clinical laboratory variables, vital signs, ECG parameters orphysical findings were detected in any of the treatment groups.

Example 7

[0096] The primary objectives of this study were to evaluate the safety,tolerability, and pharmacokinetic profile of two different, multipletopical doses of an estradiol gel including in terms of the PK variablesAUC and C_(max) with and without corrections for endogenous estradiolconcentrations in postmenopausal female subjects. Each subject receivedone of two estradiol treatments for 14 consecutive days; either 1.25 gestradiol gel 0.06% (0.75 mg estradiol/day) or 2.5 g estradiol gel 0.06%(1.5 mg estradiol/day).

[0097] Multiple doses of 0.75 mg E2/day maintained averageconcentrations (=AUC_(τ/)24) of 2.4 ng/dl (24 pg/ml). The double dose of1.5 mg E2/day resulted in an average concentration of 5.3 ng/dl (53pg/ml). The values correspond very well to those observed aftertransdermal patches such as Estraderm®. When using a patch with anominal delivery rate of 25 μg/day, an average maintenance concentrationof 23 pg/ml has been reported. For patches with a delivery rates of 50μg/day or 100 μg/day, average concentrations of 40 pg/ml and 75 pg/mlhave been reported, respectively. Estraderm® has been registered in theEuropean Community and in the United States as being efficacious forpostmenopausal disorders including reduction in hot flashes, and forosteoporosis prophylaxis. Therefore, it is predicted that the E2 gelformulation will be safe and effective for treatment of menopausalsymptoms including reduction of hot flashes, and for osteoporosisprophylaxis.

[0098] Estradiol Concentration Time Data (0-24 hours) Following a SingleDose (Day 1). FIG. 4A is a graph depicting mean serum concentrations ofestradiol (E2) following single dose administration of E2+0%LA gel(a=0.75 mg E2; b=1.50 mg E2). Following administration of the lower dose(treatment a), the concentration-time profile demonstrates that anincrease in E2 concentrations was observed. On average, E2concentrations increased from a baseline value of 0.4 ng/dl E2 at 0 H to2.1 ng/dl E2 at 24 H. Following application of the higher dose,(treatment b) an increase from 0.5 ng/dl E2 at baseline at 0 H to 3.0ng/dl E2 at 24 H was observed.

[0099] Estradiol Trough Concentration Data (Days 1-20). FIG. 4B is agraph depicting mean trough concentrations of E2 over time followingrepeated administration of E2+0%LA gel. On average, the troughconcentrations increased until approximately 24 H after application (Day2, predose). Thereafter a plateau in concentrations was observed andlevels fluctuated between 2.1 ng/dl at 24 H and 2.4 ng/dl E2 on the dayafter the last dose was applied (336 H=Day 15, 0 H). Within thissampling interval, the trough concentrations were variable andfluctuated between a minimum of 1.3 ng/dl E2 observed at 48 H (Day 3predose) to a maximum of 2.4 ng/dl at 336 H (Day 15, 0 H). Following thelast administration, average E2 concentrations declined to 0.8 ng/dl andwere near predose baseline levels (0.6 ng/dl) at 456 H (Day 20, 0 H; 5days after discontinuation of drug application).

[0100]FIG. 4D is a graph depicting individual trough concentrations ofE2 over time following repeated administration of E2+0%LA gel at bothdoses. On average, E2 concentrations continued to increase untilapproximately 240 H (Day 11 predose). Concentrations increased from 0.5ng/dl at baseline (0 H) to 8.7 ng/dl at 240 H.

[0101] The median trough values were also examined and these reached aplateau of approximately 5.1 ng/dl E2 at 96 H (Day 5 predose) afterapplication. Thereafter, the trough concentrations were variable andfluctuated between a minimum of 4.2 ng/dl E2 (median at 288 H, Day 13predose) to a maximum of 5.3 ng/dl at 336 H (Day 15, 0 H). Following thelast administration, average E2 concentrations declined to 0.8 ng/dl andwere near predose baseline levels (0.5 ng/dl) at 456 H (Day 20, 0 H; 5days after discontinuation of drug application). Examination of mediantrough concentrations indicate that steady state E2 concentrations arereached by 4 and 5 days for the E2 gel 1.25 g and 2.5 g doses,respectively.

[0102] Estradiol Concentration Time Data (0-24 hours) Following 14 Doses(Day 14). FIG. 4E is a graph depicting mean serum concentrations of E2following multiple dose administration of E2+0%LA gel. The profiles onDay 14 demonstrate that steady state E2 concentrations were reached byDay 14 (312 H). The mean E2 concentrations at the beginning of thisinterval (treatment a: 2.0 ng/dl E2, treatment b: 5.0 ng/dl E2) and atthe end of this sampling interval (treatment a: 2.4 ng/dl E2, treatmentb: 5.5 ng/dl E2) were comparable. Average maximum E2 concentrations were3.7 ng/dl and 8.8 ng/dl, respectively (Day 14 data).

[0103] Estradiol Pharmacokinetic Parameters on Day 1 and Day 14. Thepharmacokinetic parameters for E2 following single and multipleapplications of Bio-E-Gel at 1.25 g and 2.5 g are presented in Table10a. A descriptive summary of the pharmacokinetic parameters,uncorrected and baseline-adjusted, are presented in Table 10c and 10d,respectively.

[0104] Following a single application of 1.25 g of E2 gel, maximumconcentrations (C_(max)) on Day 1 were 2.3 ng/dl. On average, the timeto maximum concentrations, t_(max), was achieved by 17.67 H. Theexposure to E2, as measured by AUCτ was 27.5 ng/dl*H. Following multipleapplications, C_(max) concentrations increased to 3.7 ng/dl on Day 14.The t_(max) estimates were approximately 16 H on Day 14 and werecomparable to those observed on Day 1. The exposure to E2 was 57.0ng/dl*H on Day 14 and was higher than that observed on Day 1,demonstrating the accumulation of E2 in the serum following repeatedapplications.

[0105] Following a single application of 2.5 g of E2 gel, maximumconcentrations (C_(max)) on Day 1 were 3.7 ng/dl. On average, the timeto maximum concentrations, t_(max), was achieved by 18 H. The exposureto E2, as measured by AUCτ was 49.7 ng/dl*H. Following multipleapplication, C_(max) concentrations increased to 8.8 ng/dl on Day 14.The t_(max) estimates were approximately 18 H on Day 14 and werecomparable to those observed on Day 1. The exposure to E2 was 128.2ng/dl*H on Day 14 and was higher than that observed on Day 1,demonstrating the accumulation of E2 in the serum following repeatedapplications.

[0106] The ratio of geometric means of E2 gel 2.5 g/1.25 g was used toassess the dose proportionality of E2 following the two doses of E2 gel.After single dose application, the mean AUC ratio (E2 gel 2.5 g/1.25 g)was 38.4/19.2=2.0 and after multiple doses it was 117.6/51.9=2.3,indicating dose proportionality. TABLE 10a E2 - PK Variables by DoseRegimens 1.25 g 1.25 g 2.5 g 2.5 g Bio-E- Bio-E- Bio-E- Bio-E- Gel, Gel,Gel, Gel, Single Multiple Single Multiple Variable Statistic Dose DoseDose Dose AUC_(τ) N 6 6 6 6 [ng/dl * H] Mean 27.5 57.0 49.7 128.2 SD17.2 29.9 48.1 50.0 GeoM 19.2 51.9 38.4 117.6 G_CV 173.5 48.0 79.0 53.1C_(max) N 6 6 6 6 [ng/dl] Mean 2.3 3.7 3.7 8.8 SD 1.8 2.3 2.7 4.8 GeoM1.7 3.2 3.1 7.6 G_CV 110.1 54.2 75.9 67.0 t_(max) N 6 6 6 6 [H] Mean17.67 327.83 18.00 330.33 SD 8.62 9.85 4.90 8.62 Min 2.00 313.00 12.00314.00 Med 20.00 332.00 16.00 334.00 Max 24.00 336.00 24.00 336.00Baseline, N 6 6 6 6 C₀ Mean 0.5 0.5 0.4 0.4 [ng/dl] SD 0.4 0.4 0.3 0.3Min 0.0 0.0 0.0 0.0 Med 0.5 0.5 0.4 0.4 Max 1.3 1.3 0.8 0.8

[0107] Baseline Adjusted Estradiol Pharmacokinetic Parameters on Day 1and Day 14. Baseline concentrations of E2 were similar for both groupsand were calculated as 0.5 ng/dl and 0.4 ng/dl for the 1.25 g and 2.5 gE2 gel, respectively. In order to correct for endogenous E2concentrations, the baseline E2 concentration (E2 gel 1.25 g: 0.5 ng/dland 2.5 g: 0.4 ng/dl) was subtracted from the total concentrationmeasured after application and the AUCτ and C_(max) were recalculatedbased on the baseline-adjusted concentration. The results of thebaseline-adjusted pharmacokinetic variables are summarized in Table 10b.The baseline-adjusted C_(max) estimates were 1.8 ng/dl and 3.4 ng/dlfollowing single applications of the 1.25 g and 2.5 g E2 gel,respectively. For AUCτ, the baseline-adjusted values were 14.9 ng/dL*Hand 41.4 ng/dl*H for the 1.25 g and 2.5 g E2 gel, respectively.Following repeated applications, C_(max) estimates increased to 3.1ng/dl and 8.4 ng/dl and AUCτ estimates increased to 44.2 ng/dl*H and119.6 ng/dl*H for 1.25 g and 2.5 g E2 gel, respectively. These increasesreflect the accumulation of drug in the serum following repeatedapplication of the gel.

[0108] The terminal elimination half-life (t1/2) of E2 was calculatedfrom the baseline-adjusted concentrations following the last dose (at312 H, Day 14 predose) by log-linear regression from the linear portionof the logarithmic transformed concentration-time plot. The individualand mean estimates of half-life following the application of 1.25 g and2.5 g E2 gel are presented in Table 10d. The median half-life was 22.15H (range: 13.11-76.71) for E2 gel 1.25 g and 35.58 H (range:26.60-51.59) for 2.5 g. The half-life estimates for both treatmentgroups were comparable. TABLE 10b E2 - PK Variables, Baseline Adjusted1.25 g, 1.25 g, 2.5 g, 2.5 g, Single Multiple Single Multiple VariableStatistic Dose Dose Dose Dose δAUC_(τ) N [ng/dl * H] Mean 14.9 44.2 41.4119.6 SD 13.3 22.2 51.1 51.2 GeoM 9.8 39.7 25.2 108.9 G CV 147.3 56.1139.6 53.5 δC_(max) N 6 6 6 6 [ng/dl] Mean 1.8 3.1 3.4 8.4 SD 1.8 2.02.9 4.7 GeoM 1.2 2.7 2.4 7.3 G CV 132.8 56.4 118.5 68.5 t_(1/2) N 4 4[H] Mean 33.53 37.34 SD 29.16 12.41 Min 13.11 26.60 Med 22.15 35.58 Max76.71 51.59

[0109] Estrone Concentration Time Data (0-24 hours) Following a SingleDose (Day 1). FIG. 4F is a graph depicting mean serum concentrations ofestrone (E1) following single dose administration of E2+0%LA gel. Onaverage, E1 concentrations increased from a baseline value of 2.4 ng/dlE1 at 0 H to 3.4 ng/dl E1 at 24 H. Following application of the higherdose, (treatment b) an increase from 2.4 ng/dl E1 at baseline (0 H) to4.0 ng/dl E1 at 24 H was observed.

[0110] Estrone Trough Concentration Data (Days 1-20). FIG. 4G is a graphdepicting mean trough concentrations of E1 following repeatedadministration of E2+0%LA gel. On average, the trough concentrationsincreased to approximately 72 H (Day 4 predose) after application.Thereafter a plateau in concentrations was observed and levelsfluctuated between 4.3 ng/dl at 72 H and 5.2 ng/dl E1 on the day afterthe last dose was applied (336 H=Day 15, 0 H). Within this samplinginterval, the trough concentrations were variable and fluctuated betweena minimum of 4.1 ng/dl E1 observed at 96 H (Day 5 predose) to a maximumof 5.3 ng/dl at 288 H (Day 13 predose). Following the lastadministration, average E1 concentrations declined to 3.0 ng/dl and werenear predose baseline levels (2.4 ng/dl) at 456 H (Day 20, 0 H; 5 daysafter discontinuation of drug application).

[0111] The mean E1 trough concentrations following repeatedadministration of Bio-E-Gel 2.5 g are also presented in FIG. 4G. Onaverage, E1 concentrations continued to increase until approximately 240H (Day 11 predose). Concentrations increased from 2.4 ng/dl at baseline(0 H) to 10.4 ng/dl at 240 H. Thereafter, the trough concentrations werevariable and fluctuated between 9.1 ng/dl E1 (at 288 H=Day 13 predose)to 7.8 ng/dl at 336 H (Day 15, 0 H). Following the last administration,average E1 concentrations declined to 3.1 ng/dl and were near predosebaseline levels (4.0 ng/dl) at 456 H (Day 20, 0 H; 5 days afterdiscontinuation of drug application). Examination of mean troughconcentrations indicate that steady state E1 concentrations are reachedby 11 and 13 days for the Bio-E-Gel 2.5 g and 1.25 g doses,respectively.

[0112] Estrone Concentration Time Data (0-24 hours) Following 14 Doses(Day 14). FIG. 4H is a graph depicting mean serum concentrations of E1following multiple dose administration of E2+0%LA gel. The profiles onDay 14 demonstrate that steady state E1 concentrations were reached byDay 14 (312 H). The E1 concentrations at the beginning of this interval(treatment a: 4.8 ng/dl, treatment b: 8.2 ng/dl) and at the end of thissampling interval (treatment a: 5.2 ng/dl, treatment b: 7.8 ng/dl) werecomparable. Average maximum E1 concentrations on Day 14 (312 to 336 H)were 6.0 ng/dl and 9.2 ng/dl, respectively.

[0113] Estrone Pharmacokinetic Parameters on Day 1 and Day 14. Followinga single application of 1.25 g of E2 gel, maximum concentrations(C_(max)) on Day 1 were 3.6 ng/dl. On average, the time to maximumconcentrations, t_(max), was achieved by 12.67 H. The exposure to E1, asmeasured by AUCτ was 56.2 ng/dl*H. Following multiple applications, Cmaxconcentrations increased to 6.0 ng/dl on Day 14. The t_(max) estimateswere approximately 11 H on Day 14 and were comparable to those observedon Day 1. The exposure to E1 was 111.4 ng/dl*H on Day 14 and was higherthan that observed on Day 1, demonstrating the accumulation of E1 in theserum following repeated applications.

[0114] Following a single application of 2.5 g of E2 gel, maximumconcentrations (C_(max)) on Day 1 were 4.1 ng/dl. On average, the timeto maximum concentrations, t_(max), was achieved by 21 H. The exposureto E1, as measured by AUCτ was 62.2 ng/dl*H. Following multipleapplication, C_(max) concentrations increased to 9.2 ng/dl on Day 14.The t_(max) estimates were approximately 2 H on Day 14 and were lowerthan those observed on Day 1. The exposure to E1 was 179.7 ng/dl*H onDay 14 and was higher than that observed on Day 1, demonstrating theaccumulation of E1 in the serum following repeated applications. TABLE10c E1 - PK Variables by Dose Regimens 1.25 g 1.25 g 2.5 g 2.5 g SingleMultiple Single Multiple Variable Statistic Dose Dose Dose Dose AUC_(τ)N 6 6 6 6 [ng/dl * H] Mean 56.2 111.4 62.2 179.7 SD 31.2 54.2 30.0 67.6GeoM 49.6 100.8 56.2 167.1 G_CV 59.2 51.9 53.2 46.3 C_(max) N 6 6 6 6[ng/dl] Mean 3.6 6.0 4.1 9.2 SD 1.6 2.7 0.6 3.1 GeoM 3.2 5.6 4.0 8.7G_CV 56.3 45.0 13.2 40.5 t_(max) N 6 6 6 6 [H] Mean 12.67 323.33 21.01314.33 SD 12.42 9.93 7.33 1.51 Min 1.00 312.00 6.05 312.00 Med 13.00322.00 24.00 314.00 Max 24.00 336.00 24.00 316.00 Baseline, N 6 6 6 6 C₀Mean 1.8 1.8 2.0 2.0 [ng/dl] SD 1.4 1.4 0.9 0.9 Min 0.5 0.5 1.1 1.1 Med1.5 1.5 1.8 1.8 Max 4.4 4.4 3.2 3.2

[0115] Baseline Adjusted Estrone Pharmacokinetic Parameters on Day 1 andDay 14. Baseline concentrations of E1 were similar for both groups andwere calculated as 1.8 ng/dl and 2.0 ng/dl for the 1.25 g and 2.5 g E2gel, respectively. In order to correct for endogenous E1 concentrations,the baseline E1 concentration (E2 gel 1.25 g: 1.8 ng/dl and E2 gel 2.5g: 2.0 ng/dl) was subtracted from the total concentration measured afterapplication and the AUCτ and C_(max) were recalculated based on thebaseline-adjusted concentration. The results of the baseline-adjustedpharmacokinetic variables are summarized in Table 10d. Thebaseline-adjusted C_(max) estimates were 1.8 ng/dl and 2.0 ng/dlfollowing single applications of the 1.25 g and 2.5 g E2 gelrespectively. For AUCτ, the baseline-adjusted values were 14.5 ng/dL*Hand 17.9 ng/dl*H for the 1.25 g and 2.5 g E2 gel, respectively.Following repeated applications, C_(max) estimates increased to 4.2ng/dl and 7.2 ng/dl and AUCτ estimates increased to 67.1 ng/dl*H and131.2 ng/dl*H for 1.25 g and 2.5 g E2 gel, respectively. These increasesreflect the accumulation of drug in the serum following repeatedapplication of the gel. TABLE 10d E1 - PK Variables, Baseline Adjusted1.25 g 1.25 g 2.5 g 2.5 g Single Multiple Single Multiple VariableStatistic Dose Dose Dose Dose δAUC_(τ) N 6 6 6 6 [ng/dl * H] Mean 14.567.1 17.9 131.2 SD 5.6 27.1 6.0 68.4 Med 14.6 63.9 16.2 139.6 GeoM 13.663.0 17.2 113.8 G_CV 42.1 39.9 31.3 68.0 δC_(max) N 6 6 6 6 [ng/dl] Mean1.8 4.2 2.0 7.2 SD 0.8 1.7 0.5 3.2 Med 1.7 3.6 2.0 8.0 GeoM 1.6 4.0 2.06.4 G_CV 47.2 34.7 30.6 57.5

[0116] Estrone-Sulfate Concentration Time Data (0-24 hours) Following aSingle Dose (Day 1). FIG. 41 is a graph depicting mean serumconcentrations of estrone-sulfate (E1-sulfate) following single doseadministration of E2+0%LA gel (a=0.75 mg E2; b=1.50 mg E2). On average,E1-S concentrations increased from a baseline value of 45.8 ng/dl E1 at0 H to 79.0 ng/dl E1-S at 24 H. Following application of the higherdose, (treatment b) an increase from 34.7 ng/dl E1-S at baseline at 0 Hto 70.7 ng/dl E1-S at 24 H was observed.

[0117] Estrone-Sulfate Trough Concentration Data (Days 1-20). FIG. 4J isa graph depicting mean trough concentrations of E1-sulfate followingmultiple dose administration of E2+0%LA gel (a=0.75 mg E2; b=1.50 mgE2). On average, the trough concentrations continued to increase withrepeated applications although the mean plot suggested a change in therate of increase by approximately 192 H (Day 9 predose). E1-S serumconcentrations fluctuated between 133.8 ng/dl at 192 H and 117.8 ng/dlE1-S on the day after the last dose was applied (336 H; Day 15, 0 H).Following the last administration, average E1-S concentrations declinedto 77.0 ng/dl and were higher than predose baseline levels (45.8 ng/dl)at 456 H (Day 20, 0 H; 5 days after discontinuation of drugapplication).

[0118] On average, E1-S concentrations continued to increase untilapproximately 312 H (Day 14 predose) although a change in the rate ofincrease was evident at approximately 240 H (Day 11 predose).Concentrations increased from 34.7 ng/dl at baseline (0 H) to 193.5ng/dl at 240 H. Thereafter, the trough concentrations were variable andfluctuated between 193.5 ng/dl E1 (at 240 H) to 155.7 ng/dl at 336 H(Day 15, 0 H). Following the last administration, average E1-Sconcentrations declined to 60.3 ng/dl and were higher than predosebaseline levels (34.7 ng/dl) at 456 H (Day 20, 0 H; 5 days afterdiscontinuation of drug application). Examination of mean troughconcentrations indicate that steady state E1-sulfate concentrations arereached by 13 and 14 days for the E2 gel 1.25 g and 2.5 g doses,respectively.

[0119] Estrone-Sulfate Concentration Time Data (0-24 hours) Following 14Doses (Day 14). FIG. 4K is a graph depicting mean serum concentrationsof E1-sulfate following multiple dose administration of E2+0%LA gel. Theprofiles on Day 14 demonstrate that steady state E1-S concentrationswere essentially reached by Day 14 (312 H). The mean E1-S concentrationsat the beginning of this interval (treatment a: 130.7 ng/dl, treatmentb: 200.3 ng/dl) and at the end of this sampling interval (treatment a:117.8 ng/dl, treatment b: 155.7 ng/dl) were slightly different. However,the range of the values overlapped thereby suggesting the comparabilityof the results. Average maximum E1-S concentrations on Day 14 were 163.5ng/dl E1-S for E2 gel 1.25 g and 253.8 ng/dl E1-S for E2 gel 2.5 g.

[0120] Estrone-Sulfate Pharmacokinetic Parameters on Day 1 and Day 14.The pharmacokinetic parameters for E1-S following single and multipleapplications of E2 gel at 1.25 g and 2.5 g are presented in Table 10e. Adescriptive summary of the pharmacokinetic parameters, uncorrected andbaseline-adjusted, are presented in Table 10c and 10d, respectively.

[0121] Following a single application of 1.25 g of E2 gel, maximumconcentrations (C_(max)) on Day 1 were 80.2 ng/dl. On average, the timeto maximum concentrations, t_(max), was achieved by 20.67 H. Theexposure to E1-S, as measured by AUCτ was 1359.2 ng/dl*H. Followingmultiple applications, Cmax concentrations increased to 163.5 ng/dl onDay 14. The t_(max) estimates were approximately 5 H on Day 14 and werelower than those observed on Day 1. The exposure to E1-S was 2834.1ng/dl*H on Day 14 and was higher than that observed on Day 1,demonstrating the accumulation of E1-S in the serum following repeatedapplications.

[0122] Following a single application of 2.5 g of E2 gel, maximumconcentrations (C_(max)) on Day 1 were 74.7 ng/dl. On average, the timeto maximum concentrations, t_(max), was achieved by 20 H. The exposureto E1-S, as measured by AUCτ was 1207.4 ng/dl*H. Following multipleapplications, Cmax concentrations increased to 253.8 ng/dl on Day 14.The t_(max) estimates were approximately 3 H on Day 14 and were lowerthan those observed on Day 1. The exposure to E1-S was 4079.2 ng/dl*H onDay 14 and was higher than that observed on Day 1, demonstrating theaccumulation of E1-S in the serum following repeated applications. TABLE10e E1-Sulfate - PK Variables by Dose Regimens 1.25 g 1.25 g 2.5 g 2.5 gSingle Multiple Single Multiple Variable Statistic Dose Dose Dose DoseAUC_(τ) N 6 6 6 6 [ng/dl * H] Mean 1359.2 2834.1 1207.4 4079.2 SD 407.81219.0 243.6 1674.5 GeoM 1302.6 2611.1 1184.3 3798.7 G_CV 33.9 47.2 22.643.4 C_(max) N 6 6 6 6 [ng/dl] Mean 80.2 163.5 74.7 253.8 SD 30.5 75.512.1 124.2 GeoM 75.2 148.2 73.8 231.3 G_CV 41.5 52.6 17.0 49.0 t_(max) N6 6 6 6 [H] Mean 20.67 316.67 20.00 315.33 SD 8.16 3.93 6.20 4.46 Min4.00 314.00 12.00 312.00 Med 24.00 315.00 24.00 313.50 Max 24.00 324.0024.00 324.00 Baseline, N 6 6 6 6 C₀ Mean 51.3 51.3 36.9 36.9 [ng/dl] SD17.9 17.9 10.7 10.7 Min 23.3 23.3 23.3 23.3 Med 55.5 55.5 38.0 38.0 Max71.0 71.0 53.0 53.0

[0123] Baseline Adjusted Estrone-Sulfate Pharmacokinetic Parameters onDay 1 and Day 14. Baseline concentrations of E1-S were similar for bothgroups and were measured as 51.3 ng/dl and 36.9 ng/dl for the 1.25 g and2.5 g E2 gel, respectively. In order to correct for endogenous E1-Sconcentrations, the baseline E1-S concentration (E2 gel 1.25 g: 51.3ng/dl and Bio-E-Gel 2.5 g: 36.9 ng/dl ) was subtracted from the totalconcentration measured after application and the AUCτ and C_(max) wererecalculated based on the baseline-adjusted concentration. Thebaseline-adjusted Cmax estimates were 28.8 ng/dl and 37.7 ng/dlfollowing single applications of the 1.25 g and 2.5 g E2 gel,respectively. For AUCτ, the baseline-adjusted values were 165.7 ng/dL*Hand 325.5 ng/dl*H for the 1.25 g and 2.5 g E2 gel, respectively.Following repeated applications, C_(max) estimates increased to 112.2ng/dl and 216.9 ng/dl and AUCτ estimates increased to 1602.1 ng/dl*H and3192.5 ng/dl*H for 1.25 g and 2.5 g E2 gel, respectively. Theseincreases reflect the accumulation of drug in the serum followingrepeated application of the gel. TABLE 10f E1-Sulfate - PK Variables,Baseline Adjusted 1.25 g 1.25 g 2.5 g 2.5 g Single Multiple SingleMultiple Variable Statistic Dose Dose Dose Dose δAUC_(τ) N 6 6 6 6[ng/dl * H] Mean 165.7 1602.1 325.5 3192.5 SD 63.7 878.6 267.1 1543.4GeoM 153.9 1403.2 256.1 2893.6 G_CV 46.4 61.9 87.6 51.8 δC_(max) N 6 6 66 [ng/dl] Mean 28.8 112.2 37.7 216.9 SD 19.3 61.0 16.0 120.4 GeoM 24.197.0 33.7 192.9 G_CV 71.7 67.2 63.6 55.7

[0124] Sex Hormone Binding Globulin (SHBG). The SHBG concentrations inthe subsequent table were determined in addition to the study protocol,specially in order enable the interpretation of the unexpectedaccumulation of E2 in Subject 04. The data are tabulated in Table 10 g.Generally the mean SHBG concentrations increased with time, after E2 gel1.25 g from mean 72.5 nmol/l at 0 H over 80.17 nmol/l to 84.00 nmol/land after E2 gel 2.5 g from mean 72.5 nmol/l at 0 H over 77.83 nmol/I to88.83 nmol/l. Subject 04 who received E2 gel 2.5 g showed a similarpattern. The pre-treatment SHBG-concentrations were 58 nmol/l and 53nmol/l, respectively. 192 H (Day 9 predose) after the first applicationthe SHBG concentration was 58 nmol/l and after 360 H (Day 16, 0 H) itwas increase to 71 nmol/l. Subject 04 thus did not appear to differ fromthe other subjects and the SHBG concentration do not explain theexcessive E2 concentrations in this subject. TABLE 10g SHBG [nMol/l]Scheduled time relative to first application Treatment Statistic −16 −10192 360 E2 gel, 1.25 g N 6 6 6 6 Mean 72.33 72.50 80.17 84.00 SD 23.7324.83 28.53 29.18 GeoM 69.12 69.02 75.94 79.73 G_CV 34.09 35.54 37.5936.85 E2 gel, 2.5 g N 6 6 6 6 Mean 74.00 72.50 77.83 88.83 SD 29.6430.34 32.17 38.97 GeoM 68.91 67.20 72.20 81.17 G_CV 43.88 45.10 45.0150.71

[0125] Pharmacokinetics Conclusions. The pharmacokinetic characteristicswere calculated as surrogates for the evaluation of the efficacy. Itcould be shown that multiple doses of 0.75 mg and 1.5 mg E2 gel resultedin average serum concentrations of about 2.4 ng/dl E2 and 5.3 ng/dl E2,respectively. These values are of a magnitude which are obtained aftertransdermal patches with a delivery rate of 25 and 50 μg E2 per day andare approved for postmenopausal disorders, including reduction of hotflashes.

[0126] Safety Conclusions. Eight adverse events were observed; 7 of themwere classified as (possibly) related to the study treatments: 3 and 4events after the administration of 1.25 g and 2.5 g E2 gel,respectively. Both treatments regimens showed excellent skintolerability. No severe, serious, or significant adverse eventsoccurred. No drop outs were observed. There were no significant changesin vital signs, ECG, clinical laboratory variables or physical findings.The study medication was well tolerated. There were no relevantdifferences in safety profile of the two treatments investigated.

[0127] Conclusions. The mean and individual serum concentration-timeprofiles for E2, E1 and E1-S from 1.25 g and 2.5 g E2 gel showed thatthe two treatments provided drug concentrations that were above themeasured baseline levels. The pharmacokinetics of the gel productdemonstrate that upon repeated administration a plateau in drug levelsis generally reached. In addition, once drug is discontinued, druglevels return to or are near baseline levels within 5 days. Thepharmacokinetics of E2, E1 and E1-S suggested dose proportionality forthe 1.25 and 2.5 g gel products. Mean parameter estimates in the 2.5 gtreatment group were approximately double the estimates in the 1.25 gtreatment group on Days 1 and 14.

[0128] Estimates of t_(max) were variable in both treatment groups. Atsteady-state on Day 14, some estimates of t_(max) occurred at thebeginning of the dosing interval. In these cases, it is possible thatserum concentrations continued to rise immediately after a dose due tocontinued presence of drug from the previously administered dose. Thetime to maximum concentration following administration of bothtreatments occurred within 16-20 H after the first application.

[0129] The achievement of steady-state was assessed primarily bygraphical methods. Mean trough concentrations for E2 in both treatmentgroups were highly variable but showed no significant increasing trendover the study period. The median trough concentration plots suggestedthat steady-state was reached for E2 by Day 5 in both treatment groups.Based upon the estimates of t1/2 for E2 obtained in this study(approximately 33 H), steady-state would be achieved after approximately9 to 10 days of dosing, a finding which is consistent with the resultsof the graphical analysis. Thus, the pharmacokinetic measurementsconducted on Day 14 of treatment should be representative ofsteady-state. Similar results were observed for E1 and E1-S althoughconcentrations did appear to be more variable and to fluctuate more forthese two analytes.

[0130] The pharmacokinetic characteristics were calculated as surrogatesfor the evaluation of the efficacy. It could be shown that multipledoses of 0.75 mg and 1.5 mg E2 gel resulted in average serumconcentrations of about 2.4 ng/dl E2 and 5.3 ng/dl E2, respectively.These values are of a magnitude, which are obtained after transdermalpatches with a delivery rate of 25 and 50 μg E2 per day and are approvedfor postmenopausal disorders, including reduction of hot flashes andosteoporosis. Therefore, it is predicted that E2 gel will be proven safeand effective for treatment of menopausal symptoms including reductionof hot flashes and osteoporosis.

Example 8

[0131] Study of the Safety and Efficacy of Topical E2 Gel Versus Placebofor Treatment of Vasomotor Symptoms in Postmenopausal Females. Theobjectives of this study were to evaluate the safety and efficacy, anddetermine the lowest effective dose of E2 gel, administered as a dailyregimen, as compared to that of placebo gel in the treatment ofvasomotor symptoms in postmenopausal women. Eligible subjects wereequally randomized to one of four treatment arms: E2 gel 0.625/day(0.375 mg estradiol), E2 gel 1.25 g/day (0.75 mg estradiol), E2 gel 2.5g/day (1.5 mg estradiol) or matching placebo gel. Eligible subjects werehealthy postmenopausal women, with an estradiol level <20 pg/mL, whoexhibited ≧7 moderate to severe hot flushes each day or ≧60 moderate tosevere hot flushes total during 7 days of screening.

[0132] E2 gel consisted of 0.06% estradiol in a hydroalcoholic gelformulation supplied in single-dose sachets: E2 gel 0.625 g/day (0.375mg/day E2), E2 gel 1.25 g/day (0.75 mg/day E2), or E2 gel 2.5 g/day (1.5mg/day E2). Daily topical applications of E2 gel was administered by thesubject on the thigh.

[0133] Parameters were evaluated including: hot flush occurrence ratesand severity. Adverse events, safety laboratory tests, vitals signs,weight, physical examinations, breast examinations, skin irritation wereassessed.

[0134] Results of the primary analyses of the co-primary efficacyendpoints indicate that the lowest effective dose of E2 gel in thetreatment of vasomotor symptoms in postmenopausal women is E2 gel 2.5g/day (1.5 mg/day E2). In the E2 gel 2.5 g/day treatment group, thedifference from placebo of 2.7 in mean change from baseline in themoderate-to-severe hot flush rate at Week 4 was clinically meaningful(i.e., ≧2.0), with a complimentary superiority to placebo in mean changefrom baseline in daily hot flush mean severity (placebo −0.6; E2 gel 2.5g/day, −0.9). The analogous differences from placebo in daily hot flushrate for the other E2 gel dose groups were not clinically meaningful (E2gel 0.625 g/day, 0.7; E2 gel 1.25 g/day, 0.0). TABLE 11 DailyModerate-to-Severe Hot Flush Rates: Mean Change from Baseline^(a) E2 GelE2 Gel E2 Gel Placebo 0.625 g/day 1.25 g/day 2.5 g/day Evaluation (N =42) (N = 41) (N = 39) (N = 38) Baseline 16.0 ± 9.88 12.5 ± 5.60 12.3 ±7.26 13.0 ± 5.97 (Mean ± SD)^(b) Week −1 −5.3 −3.9 −4.7 −5.0 (PlaceboLead-In) Week 1 −7.3 −5.8 −5.9 −7.5 Week 2 −7.9 −7.5 −7.2 −9.4 Week 3−8.5 −8.5 −7.4 −10.5 Week 4 −8.5 −9.2 −8.5 −11.2

[0135] As in the primary efficacy analyses, comparison of treatmentgroups with respect to the proportion of subjects with a ≧90% reductionin daily moderate-to-severe hot flush rate at Week 4 indicateseffectiveness in the E2 gel 2.5 g/day group (55% of subjects), while theother E2 gel dose groups performed similar to placebo (27% to 35%).Furthermore, the median estradiol concentration at Week 4 for the E2 gel2.5 g/day dose group (33 pg/mL) is in the low end of the expectedtherapeutic range, with the median concentrations falling below therange for the other E2 gel dose groups (E2 gel 0.625 g/day, 12 pg/mL; E2gel 1.25 g/day, 23 pg/mL).

[0136] Analyses of Efficacy. The primary efficacy evaluation of theclinical effectiveness of E2 gel 0.625 g/day (0.375 mg E2), E2 gel 1.25g/day (0.75 mg E2), and E2 gel 2.5 g/day (1.5 mg E2) as compared toplacebo was determined with respect to change from baseline in daily(moderate-to-severe) hot flush rate at Week 4 and change from baselinein daily hot flush mean severity at Week 4 evaluated in the ITT LOCFData Set. The baseline measures used in these analyses are based on dataobtained during the Screening Period analyses with baseline measuresbased on data obtained during the Placebo Lead In Period were notincluded.

[0137] The primary analysis of change from baseline in daily hot flushmean severity was based on unadjusted means from the one-way ANOVA modelwith treatment as the factor. However, in consideration of dissimilarityacross treatment groups with respect to mean baseline daily hot flushrates, as well as an apparent treatment-by-site interaction, the primaryanalysis of change from baseline in daily hot flush rate was based onleast-squares means derived from the ANCOVA model with factors fortreatment, site, and treatment-by-site interaction, with baseline hotflush rate as the covariate. Only these primary analysis results arediscussed.

[0138] As secondary efficacy analyses, the analyses of the 2 co-primaryendpoints described above were performed on the Evaluable Subject LOCFData Set. Additional analyses included the proportions of subjects whohad a ≧50%, ≧60%, ≧70%, ≧80%, ≧90%, ≧95% or 100% reduction from baselinein daily moderate-to-severe hot flush rate at Week 4, conducted for theITT LOCF and the Evaluable Subject LOCF Data Sets. For the ITT Data Set,the results of these proportion analyses are presented in a text table.

[0139] Descriptive analyses of the 2 co-primary endpoints were performedfor the ITT Observed-Case Data Set and the Evaluable SubjectObserved-Case Data Set at Week 1, Week 2, Week 3, and Week 4. Since only4 subjects discontinued treatment prematurely, the results of theobserved-case analyses on these data sets are nearly identical to thosefrom the LOCF analyses and are therefore not discussed explicitly inthis report.

[0140] Mean Change from Baseline in Daily Moderate-to-Severe Hot FlushRates. Intent-to-Treat Data Set—LOCF Analyses. In the LOCF analyses ofthe ITT Data Set, mean reductions from baseline in dailymoderate-to-severe hot flush rates were observed for all four treatmentgroups, with a more pronounced reduction observed in the E2 gel 2.5g/day dose group (see Table 11a and FIG. 5a).

[0141] A clinically significant difference (i.e., >2.0) was observedbetween the E2 gel 2.5 g/day group and placebo in the mean reduction ofdaily hot flush rate at Week 4 (difference between groups =−2.7), whilethe two lower doses of E2 gel did not show a clinically meaningfuldifference from placebo. Therefore, the two lower E2 gel doses arenon-effective and the E2 gel 2.5 g/day dose is demonstrated to be thelowest effective dose for the treatment of moderate-to-severe hotflushes.

[0142]FIG. 5A is a graph depicting mean change from baseline in dailymoderate-to-severe hot flush rate after estradiol at various doses(ITT-LOCF). TABLE 11a Mean Change from Baseline in DailyModerate-to-Severe Hot Flush Rate (ITT-LOCF) Mean Change from BaselineE2 Gel E2 Gel E2 Gel Placebo 0.625 g/day 1.25 g/day 2.5 g/day Evaluation(N = 42) (N = 41) (N = 39)^(b) (N = 38)^(c) Baseline 16.0 ± 9.88 12.5 ±5.60 12.3 ± 7.26 13.0 ± 5.97 (Mean ± SD)^(d) Week −1 −5.3 −3.9 −4.7 −5.0(Placebo Lead-In) Week 1 −7.3 −5.8 −5.9 −7.5 Week 2 −7.9 −7.5 −7.2 −9.4Week 3 −8.5 −8.5 −7.4 −10.5 Week 4 −8.5 −9.2 −8.5 −11.2

[0143] Evaluable Subject Dataset—LOCF Analyses. In the LOCF analyses ofthe Evaluable Subject Data Set, mean reductions from baseline in dailymoderate-to-severe hot flush rates were observed for all 4 treatmentgroups, with a more pronounced reduction observed in the E2 gel 2.5g/day dose group (see Table 11b and FIG. 5b). A clinically significantdifference (i.e., ≧2.0) was observed between the E2 gel 2.5 g/day dosegroup and placebo in the mean reduction of daily hot flush rate at Week4 (difference between groups =^(˜)−3.2), while the two lower doses of E2gel did not show a clinically meaningful difference from placebo.

[0144]FIG. 5B is a graph depicting mean change from baseline in dailymoderate-to-severe hot flush rate after estradiol at various doses(Evaluable-LOCF). TABLE 11b Mean Change from Baseline in DailyModerate-to-Severe Hot Flush Rate (Evaluable-LOCF) Mean Change fromBaseline^(a) E2 Gel E2 Gel E2 Gel Placebo 0.625 g/day 1.25 g/day 2.5g/day Evaluation (N = 28) (N = 38) (N = 33) (N = 30) Baseline 15.3 ±9.35 12.3 ± 5.11 12.8 ± 7.73 13.4 ± 5.91 (Mean ± SD)^(b) Week −1 −4.8−3.7 −5.0 −4.8 (Placebo Lead-In) Week 1 −6.7 −5.9 −6.0 −7.6 Week 2 −7.1−7.6 −7.3 −9.4 Week 3 −7.9 −8.5 −7.6 −10.6 Week 4 −8.0 −9.1 −9.0 −11.2

[0145] Proportion of Subjects with ≧90% or 100% Percent Reductions inDaily Moderate-to-Severe Hot Flush Rates at Week 4. Intent-to-Treat DataSet—LOCF Analyses. In the LOCF analyses of the ITT Data Set, themajority (55%, 21/38) of subjects in the E2 gel 2.5 g/day dose groupexperienced a ≧90% reduction in daily moderate-to-severe hot flush rateat Week 4, compared to approximately a third of subjects in placebo andthe two lower E2 gel dose groups (see Table 11c). Twenty-four percent(24%) of subjects in the E2 gel 2.5 g/day dose group had a 100%reduction (i.e., no moderate-to-severe hot flushes) at Week 4. TABLE 11cNumber and Proportion of Subjects with a ≧50% to a 100% Reduction inDaily Moderate-to-Severe Hot Flush Rates at Week 4 (ITT-LOCF) Number (%)of Subjects E2 Gel E2 Gel E2 Gel Placebo 0.625 g/day 1.25 g/day 2.5g/day Evaluation (N = 42) (N = 41) (N = 39)^(a) (N = 38) ≧50% Reduction32 (76%) 31 (76%) 32 (82%) 33 (87%) ≧60% Reduction 29 (69%) 29 (71%) 28(72%) 32 (84%) ≧70% Reduction 24 (57%) 21 (51%) 23 (59%) 29 (76%) ≧80%Reduction 19 (45%) 15 (37%) 17 (44%) 24 (63%) ≧90% Reduction 13 (31%) 11(27%) 14 (36%) 21 (55%) ≧95% Reduction  8 (19%)  7 (17%) 12 (31%) 19(50%) 100% Reduction  4 (10%)  4 (10%)  8 (21%)  9 (24%)

[0146] Mean Change from Baseline Severity of Hot Flushes.Intent-to-Treat Data Set—LOCF Analyses. In the LOCF analyses of the ITTData Set, mean reductions from baseline daily hot flush mean severitywere observed for all four treatment groups, with a more pronouncedreduction observed in the E2 gel 2.5 g/day dose group, and to a lesserdegree, in the E2 gel 1.25 g/day dose group (see Table 11d and FIG. 5c).The decrease in daily hot flush mean severity over time in the E2 gel2.5 g/day dose group is complimentary to the clinically meaningfuldifference from placebo seen at Week 4 in mean reduction of daily hotflush rate.

[0147]FIG. 5C is a graph depicting mean change from baseline in dailyhot flush mean severity after estradiol at various doses (ITT-LOCF).TABLE 11d Mean Change from Baseline in Daily Hot Flush Mean Severity(ITT-LOCF) Mean Change from Baseline^(a) E2 Gel E2 Gel E2 Gel Placebo0.625 g/day 1.25 g/day 2.5 g/day Evaluation (N = 42) (N = 41) (N =39)^(b) (N = 38)^(c) Baseline 2.3 ± 0.31 2.2 ± 0.30 2.3 ± 0.33 2.2 ±0.33 (Mean ± SD)^(d) Week −1 −0.2 −0.2 −0.2 −0.1 (Placebo Lead-In) Week1 −0.5 −0.2 −0.3 −0.3 Week 2 −0.6 −0.3 −0.5 −0.6 Week 3 −0.6 −0.4 −0.6−0.7 Week 4 −0.6 −0.6 −0.8 −0.9

[0148] Drug Dose, Drug Concentration, and Relationships to Response.Estradiol, Estrone, and Estrone Sulfate. Trough serum samples wereobtained prior to dosing on Day 1 and upon study completion fordetermination of estradiol, estrone, and estrone sulfate concentrations.For summarization, all assay results below the detection limit of 5pg/mL were set equal to the limit (i.e., assigned a value of 5 pg/mL).Trough concentrations of estradiol, estrone, and estrone sulfate at Day1 and Week 4 were highly variable within treatment groups (see Table11e). In consideration of the variability and the moderate sample sizes,median values will be discussed.

[0149] Across all treatment groups, median values at Day 1 for estradiol(5 pg/mL), estrone (18.5 to 22.0 pg/mL), and the estradiol-to-estroneratio (0.29 to 0.42) were consistent with a postmenopausal profile (seeTable 11e). However, note that some subjects who met the inclusioncriterion of <20 pg/mL estradiol at screening failed to meet thiscriterion at Day 1. Apart from variability inherent to the assay,speculative reasons for this are instability of hormone levels forsubjects with menopause onset within the prior year, hysterectomywithout oopherectomy in subjects <50 years of age, or possibleunreported noncompliance regarding use of an estrogen product during theScreening Period.

[0150] After therapy with E2 gel, median estradiol, estrone, and estronesulfate concentrations at Week 4 showed separation between treatmentgroups in accord with E2 gel dose administration (see Table 11e). Themedian estradiol values at Week 4 were 12 pg/mL, 23 pg/mL, and 33 pg/mL,respectively, for the E2 gel 0.625 g/day, 1.25 g/day, and 2.5 g/day dosegroups. TABLE 11e Trough Estradiol, Estrone, and Estrone Sulfate at Day1 and Week 4 (ITT) E2 Gel E2 Gel E2 Gel Hormone Evaluation Placebo 0.625g/day 1.25 g/day 2.5 g/day E2 (pg/mL) Day 1 (N = 41) (N = 41) (N = 39)(N = 38) Mean ± SD 12.2 ± 18.5 15.3 ± 24.5 10.3 ± 13.5 12.3 ± 20.3Median  5   5   5   5  Range  5-110  5-120  5-64  5-110 Week 4 (N = 40)(N = 41) (N = 37) (N = 37) Mean ± SD 11.4 ± 15.4 24.1 ± 41.6 34.8 ± 33.046.8 ± 44.6 Median  5  12  23  33  Range  5-85  5-240  5-170  5-250 E1(pg/mL) Day 1 (N = 41) (N = 41) (N = 39) (N = 38) Mean ± SD 22.3 ± 13.929.9 ± 28.1 24.3 ± 15.8 22.4 ± 13.9 Median  19.0  22.0  22.0  18.5 Range5-65 6-160 5-93 5-67 Week 4 (N = 40) (N = 41) (N = 37) (N = 36) Mean ±SD 21.6 ± 15.3 36.3 ± 15.7 51.9 ± 29.1 72.3 ± 43.8 Median  19.5  35.0 44.0  60.5 Range  5-82  5-78  13-130  17-200 E2/E1 Ratio Day 1 (N = 41)(N = 41) (N = 39) (N = 38) Mean ± SD 0.55 ± 0.52 0.49 ± 0.36 0.43 ± 0.290.47 ± 0.33 Median   0.42   0.31   0.29   0.39 Range 0.2-2.9 0.0-1.60.1-1.2 0.2-2.0 Week 4 (N = 40) (N = 41) (N = 37) (N = 36) Mean ± SD0.59 ± 0.59 0.55 ± 0.56 0.67 ± 0.59 0.64 ± 0.33 Median   0.37   0.35  0.51   0.54 Range 0.2-3.2 0.2-3.3 0.2-3.8 0.2-1.7 E1-S (pg/mL) Day 1(N = 41) (N = 41) (N = 39) (N = 38) Mean ± SD 532.4 ± 350.2 691.0 ±815.5 457.4 ± 193.9 523.2 ± 443.5 Median 410.0 480.0 430   430.0 Range 150-2100  170-4760 190-940  180-2650 Week 4 (N = 40) (N = 40) (N = 38)(N = 36) Mean ± SD   573 ± 616.6 944.4 ± 579.1 1562 ± 1610 2283 ± 1884Median 400.0 740.0 995.0 1765   Range  110-4020  300-2870  280-8020 330-7040

[0151] Safety Conclusions. Daily application of 0.625-2.5 g E2 gel(0.375-1.5 mg estradiol) for approximately 4 weeks was safe andwell-tolerated in this population of postmenopausal females. The overallincidence of treatment-emergent adverse events among the E2 gel groupswas not increased with dose level (approximately 50% in each dosegroup), and compared well to the incidence in the placebo group (40%).Adverse events associated with reproductive system and breast disorderswere reported more frequently in the E2 gel groups (10%, 18%, and 13% inthe 0.625 g/day, 1.25 g/day, and 2.5 g/day E2 gel groups, respectively)versus placebo (5%), as would be expected in this class of drugs. Theseevents reported in 2 or more E2 gel subjects included: breasttenderness, metrorrhagia (vaginal spotting), nipple pain, uterine spasm,and vaginal discharge. No relationship was apparent between theincidence of these events and E2 gel dose or estradiol level. Nosubjects discontinued the study due to these events.

[0152] Breast examination indicated no effect of E2 gel at finalevaluation for all but one subject; the change observed for this subject(E2 gel 2.5 g/day) corresponded to one of the reported adverse events ofmild breast tenderness, which resolved one week after final study drugadministration.

[0153] No deaths or serious adverse events occurred during the study.Two (2) subjects (both E2 gel 1.25 g/day) discontinued double-blindtreatment due to an adverse event, only one of which (dizziness) wasconsidered possibly related; both subjects recovered.

[0154] No clinically meaningful effects of E2 gel on clinical laboratoryresults were observed in analyses of mean change from baseline to Week 4evaluations. Comparisons of proportions of subjects with shifts fromnormal baselines to abnormal levels at Week 4 indicated a higherincidence of shifts to above normal cholesterol levels in E2 gel groups,and an apparent E2 gel dose-related increased incidence of shifts toabove normal BUN levels; however, only about 10 subjects per group wereincluded in the cholesterol comparison (since most subjects had abovenormal baseline cholesterol levels), and the BUN shifts were notassociated with corresponding shifts in other renal function indicatorsor clinical manifestations of renal insufficiency.

[0155] No clinically important effects of E2 gel were observed for vitalsigns, body weight, physical examinations, or skin irritationassessment.

[0156] Conclusion. Transdermal ET delivers estradiol directly into thesystemic circulation via the skin, thus avoiding the first-pass hepaticmetabolism that occurs with oral ET and avoiding the effects on thehepatobiliary system seen with oral ET. No statistically significant orclinically meaningful changes noted in the mean change from baseline toWeek 4 evaluation were observed for any liver function parameters. Onesubject in the E2 gel 0.625 g/day dose group experienced an increasedAST that the investigator felt was clinically significant; also thissubject had an elevated ALT (44 u/L) at baseline that increased to 70u/L at final evaluation. No subjects were observed to have clinicallysignificant increases in liver function tests in the E2 gel 1.25 g/dayor E2 gel 2.5 g/day dose groups.

[0157] Adverse events associated with the topical application of thestudy gel were minimal and were more frequently reported in the E2 gel1.25 g/day dose group. Dry skin at the application site was the mostfrequently reported event associated with the application of study drug,occurring in two subjects. These events were considered mild, with theonset greater than 2 weeks on study drug, and the events lasted nolonger than 7 days. Other skin related events reported included burningor itching at the application site, occurring in one subject for eachevent. No treatment-emergent erythema at application site occurred.

[0158] Oral ET has been shown to produce an increase in the biliarycholesterol saturation index, and is associated with an increased riskof gallstones disease; however, this effect does not appear to beevident in transdermal ET. No subjects in the E2 gel dose groups werenoted to have clinically significant changes in bilirubin levels, and noadverse events related to increased cholesterol, bilirubinemia, orgallstones were reported.

[0159] While it was initially thought that the use of transdermal ETwould avoid the increases in serum lipids and lipoproteins seen withoral ET, studies have shown that changes in serum lipids andlipoproteins do occur, but with onset and progression that is slowerthan with oral ET. In this 4 week study, clinically meaningful meanchanges were not observed in these parameters, though overall changeswould not be expected in just a 4-week duration of treatment. Onesubject in the E2 gel 2.5 g/day dose group had a clinically significantchange from baseline in triglycerides; however, the subject's finallaboratory blood draw was non-fasting. Incidentally, this subject'sbaseline cholesterol was 287 mg/dL and LDL was 172 mg/dL.

[0160] The results of this study demonstrate that E2 gel administereddaily in doses of 0.625-2.5 g/day for 4 weeks is safe andwell-tolerated.

[0161] The particular embodiments of the invention having been describedabove are not limiting of the present invention, and those of skill inthe art can readily determine that additional embodiments and featuresof the invention are within the scope of the appended claims andequivalents thereto.

[0162] While the specification describes particular embodiments of thepresent invention, those of ordinary skill can devise variations of thepresent invention without departing from the inventive concept. Thus,the invention described and claimed herein is not to be limited in scopeby the specific embodiments disclosed herein, since these embodimentsare intended as illustrations of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of theinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description. Such modifications are alsointended to fall within the scope of the appended claims.

What is claimed is:
 1. A formulation for transdermal or transmucosaladministration of an active agent, the formulation comprising: at leastone active agent, provided that when the active agent is an estrogen orprogestin, a therapeutically effective amount of a progestin orestrogen, respectively, is not present in the formulation; and adelivery vehicle comprising a C₂ to C₄ alkanol, a polyalcohol, and apermeation enhancer of monoalkyl ether of diethylene glycol present inan amount sufficient to provide permeation enhancement of the activeagent through dermal or mucosal surfaces; wherein the formulation issubstantially free of long-chain fatty alcohols, long-chain fatty acids,and long-chain fatty esters in order to avoid undesirable odor andirritation effects caused by such compounds during use of theformulation.
 2. The formulation of claim 1, wherein the polyalcohol ispresent in an amount between about 1% and 30% of the vehicle; and thepermeation enhancer is present in an amount of between about 0.2% and25% of the vehicle.
 3. The formulation of claim 1, wherein the activeagent is testosterone present in an amount between about 0.05% to 10% ofthe formulation; the alkanol is present in an amount between about 20 to65% of the formulation; the polyalcohol is propylene glycol present inan amount between about 1% to 15% of the formulation; the permeationenhancer is diethylene glycol monoethyl ether present in an amountbetween about 1% to 15% of the formulation, and further wherein theformulation comprises a gelling agent present in an amount of between0.05% to about 4% of the formulation, a neutralizing agent present in anamount between about 0.05% and 1% of the formulation, and water presentin an amount between about 20% to 65% of the formulation.
 4. Theformulation of claim 3, wherein the formulation further includes asequestering agent.
 5. The formulation of claim 1, wherein thepolyalcohol and permeation enhancer are present in a weight ratio of 2:1to 1:1.
 6. The formulation of claim 1, wherein the polyalcohol andpermeation enhancer are present in a weight ratio of 1.25:1 to 1.2:1. 7.The formulation of claim 1, wherein the alkanol is present in an amountof 5 to 75% by weight of the vehicle.
 8. The formulation of claim 1,wherein the alkanol is selected from the group consisting of ethanol,isopropanol and n-propanol.
 9. The formulation of claim 1, wherein thepolyalcohol is polypropylene glycol.
 10. The formulation of claim 1wherein the active agent is selected from the group including androgens,estrogens, or progestogens or any combination thereof.
 11. Theformulation of claim 1, wherein the active agent is selected from thegroup consisting of androgens, anti-androgens, estrogens,anti-estrogens, progestogens, anti-progestogens, adrenergic agonists,analgesics, sedatives, amides, arylpiperazines, nerve agents,antineoplastics, anti-inflammatory agents, anticholinergics,anticonvulsants, antidepressants, antiepileptics, antihistaminics,antihypertensives, muscle relaxants, diuretics, bronchodilators, andglucocorticoids.
 12. The formulation of claim 1, wherein the at leastone active agent is in combination with a secondary active agent forconcurrent administration.
 13. The formulation of claim 12, wherein theat least one or secondary active agent is a combination ofmethyltestosterone and esterified estrogen.
 14. The formulation of claim12, wherein the at least one or secondary active agent is a combinationof testosterone and nandrolone decanoate.
 15. The formulation of claim12, wherein the at least one or secondary active agent is a combinationof testosterone and estradiol.
 16. The formulation of claim 1, whereinthe formulation further comprises at least one of a gelling agent,neutralizing agent, sequestering agent, buffering agent, moisturizingagent, humectant, surfactant, antioxidant, emollient, or buffer.
 17. Theformulation of claim 16, wherein the gelling agent is selected from thegroup consisting of carbomer, carboxyethylene, polyacrylic acid,cellulose derivatives, ethylcellulose, hydroxypropylmethylcellulose,ethylhydrooxyethylcellulose, carboxymethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, natural gums, arabic,xanthan, guar gums, alginates, polyvinylpyrrolidone derivatives,polyoxyethylene polyoxypropylene copolymers, chitosan, polyvinylalcohol, pectin, and veegum.
 18. The formulation of claim 16, whereinthe buffering agent is selected from the group consisting of carbonatebuffers, citrate buffers, phosphate buffers, acetate buffers,hydrochloric acid, lactic acid, tartric acid, diethylamine,triethylamine, diisopropylamine, tetrahydroxypropylethylendiamine, andaminomethylamine.
 19. The formulation of claim 16, wherein thesequestering agent is edetic acid.
 20. The formulation of claim 1wherein the formulation is in the form of a gel, lotion, cream, spray,aerosol, ointment, emulsion, suspension, liposomal system, lacquer,patch, bandage, or occlusive dressing.
 21. A formulation for transdermalor transmucosal administration of an active agent, the formulationcomprising: at least one active agent, provided that when the activeagent is an estrogen or progestin, a therapeutically effective amount ofa progestin or estrogen, respectively, is not present in theformulation; and a delivery vehicle comprising a C₂ to C₄ alkanol, apolyalcohol, and a permeation enhancer of monoalkyl ether of diethyleneglycol to provide permeation enhancement of the active agent throughdermal or mucosal surfaces, wherein the polyalcohol is propylene glycoland is present in an amount between about 1% and 30% of the vehicle, thepermeation enhancer is diethylene glycol monoethyl ether and is presentin an amount of between about 0.2% and 25% of the vehicle, the alkanolis ethanol and is present in an amount of 5 to 75% by weight of thevehicle wherein the formulation is substantially free of long-chainfatty alcohols, long-chain fatty acids, and long-chain fatty in order toavoid undesirable odor and irritation effects caused by such compoundsduring use of the formulation.
 22. The formulation of claim 21, whereinthe polyalcohol and permeation enhancer are present in a weight ratio of2:1 to 1:1.
 23. The formulation of claim 1 wherein the formulationcomprises at least one of a gelling agent, neutralizing agent,sequestering agent, buffering agent, moisturizing agent, humectant,surfactant, antioxidant, emollient, or buffer and is in the form of agel, lotion, cream, spray, aerosol, ointment, emulsion, suspension,liposomal system, lacquer, patch, bandage, or occlusive dressing.
 24. Aformulation for epithelial administration of an active agent, theformulation comprising: at least one active agent comprising anandrogen; and a delivery vehicle comprising a C₂ to C₄ alkanol, apolyalcohol, and a permeation enhancer of monoalkyl ether of diethyleneglycol present in an amount sufficient to provide permeation enhancementof the active agent through epidermal surfaces; wherein the formulationis substantially free of long-chain fatty alcohols, long-chain fattyacids, and long-chain fatty esters in order to avoid undesirable odorand irritation effects caused by such compounds during use of theformulation.
 25. The formulation of claim 24, wherein the alkanol isethanol, the polyalcohol is propylene glycol, and the permeationenhancer is monoethyl ether of diethylene glycol.
 26. The formulation ofclaim 24, wherein the formulation is in the form of a gel.